US20040175761A1

US20040175761A1 - Voltage sensor domains of voltage-dependent ion channel proteins and uses thereof

Info

Publication number: US20040175761A1
Application number: US10/377,139
Authority: US
Inventors: Roderick MacKinnon; Alice MacKinnon; Youxing Jiang; Vanessa Ruta
Original assignee: Individual
Current assignee: Rockefeller University
Priority date: 2003-03-01
Filing date: 2003-03-01
Publication date: 2004-09-09
Also published as: US8283126B2; US20110159599A1; US7405052B2; US20090075394A1; WO2004079337A3; WO2004079337A2; US7888046B2

Abstract

A composition of matter suitable for use in identifying chemical compounds that bind to voltage-dependent ion channel proteins, the composition comprising a screening protein that comprises an ion channel voltage sensor domain of the ion channel protein immobilized on a solid support.

Description

BACKGROUND OF THE INVENTION

Many cells produce electrical impulses known as electrical activities (e.g., action potential) that propagate across their surface membrane. Action potentials travel quickly, and their arrival at a distant location initiates cellular processes such as the release of neurotransmitter molecules or the contraction of muscles (Hille B. Ion Channels of Excitable Membranes. Sinauer Associates, Inc. Sunderland, Mass., 2001). These electrical impulses are the means by which living cells transfer information over large distances in short time intervals.

Action potential theory contains two key elements (Hodgkin et al. J. Physiol. (Lond) 1952,117:500-544). The first element is that the membrane of a cell can undergo transient changes in its selective permeability to, for example, Na⁺ and K⁺ ions. The second element is that the permeability changes depend on membrane voltage. These two elements create an interesting situation because selective permeability to ions determines the membrane voltage, while the voltage determines the permeability.

The family of protein molecules known as the voltage-dependent cation channels typically mediate electrical activity. This family includes potassium (K ⁺), sodium (Na⁺) and calcium (Ca²⁺ ) selective members. The opening of a pore of a voltage-dependent ion channel, a process known as gating, is dependent upon the membrane voltage. When the pore of a voltage-dependent cation channel opens, it selectively conducts predominantly its namesake ion.

It is believed that charged amino acids, called gating charges, move through the membrane electric field before the pore opens, allowing membrane voltage to bias the equilibrium between closed and opened conformations (Armstrong et al. J. Gen. Physiol. 1974, 63:533-552; Sigworth et al. Q. Rev. Biophys. 1994, 27:1-40; and Bezanilla Physiol. Rev. 2000, 80:555-592).

In K ⁺ channels, the gating charge per tetrameric channel corresponds to 12-14 electron charges (3.0-3.5 charges per subunit) crossing the entire membrane voltage difference. This large gating charge gives rise to a steep change in open probability as a function of membrane voltage.

All members of the voltage-dependent cation channel family typically contain six hydrophobic segments, S 1 through S6 (S1-S6) (see FIGS. 1 and 2), per subunit. Four subunits (most often identical in K+ channels and linked together as homologous ‘domains’ in Na⁺ and Ca2⁺ channels) surround a central ion conduction pore. S5 through S6 line the pore and determine ion selectivity, while S1 through S4 form the voltage sensors. Certain charged amino acids within the voltage sensors account for most of the gating charge. These amino acids are particularly the first four arginines in S4.

Voltage-dependent ion channels are present in every cell and are involved in generation of electrical activity and information processing. As such, aberrant electrical activity can result in various conditions, such as heart arrhythmias, epilepsy, hypertension, etc.

There is a need for a composition and method for rapidly screening chemical compounds to determine whether the compounds bind to voltage-dependent ion channels.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a composition of matter suitable for use in identifying chemical compounds that bind to voltage-dependent ion channel proteins. The composition comprises a screening protein that comprises an ion channel voltage sensor domain of the ion channel protein immobilized on a solid support.

In another embodiment, the invention relates to a kit suitable for use in identifying chemical compounds that bind to voltage-dependent ion channel proteins. The kit comprises a screening protein that comprises an ion channel voltage sensor domain of the ion channel protein and a solid support.

In another embodiment, the invention relates to a labeled screening protein suitable for use in identifying chemical compounds that bind to a voltage-dependent ion channel protein. The labeled screening protein comprising an ion channel voltage sensor domain of the ion channel protein and a detectable label.

In another embodiment, the invention relates to a method for screening for drug candidates that a target voltage dependent ion channel protein. The method comprises providing a screening protein, contacting the screening protein with a chemical compound, determining whether the chemical compound binds to the screening protein, wherein chemical compounds that bind to the screening protein are drug candidates.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Sequences of prokaryotic and eukaryotic voltage-dependent potassium (Kv) channels. Regions of high homology are colored in grey; functionally important residues are colored dark grey. Alignment was made with ClustalW followed by manual adjustment and exclusion of loops. The potassium channels are: Apernix, [0013] Aeropyrum pernix(Genbank Accession number GI: 5104624); Paeru, Pseudomonas aeruginosa(Genbank Accession number GI: 15596693); Dradio, Deinococcus radiodurans (Genbank Accession number GI: 15805856); Shaker, Drosophila melanogaster (Genbank Accession number GI: 13432103); RatKv2.1, Rattus norvegicus (Genbank Accession number GI: 24418849); HsapKv4.3, Homo sapiens (Genbank Accession number GI: 5059060). The sequences corresponding to the above Genbank Accession numbers are hereby incorporated by reference.
FIG. 2. Architecture of a voltage-dependent potassium channel. A) Transmembrane-spanning segments (S[0014] 1-S6) are labelled; B) four subunits surround the pore. S1-S4 form the voltage sensor and S5-S6, including P, form the pore, represented by the KcsA potassium channel structure (backbone model).
FIG. 3. Functional and structural analysis of the isolated voltage sensor domain. A) The isolated voltage sensor retains its ability to bind tarantula toxins that specifically inhibit voltage sensors. Quantitative reverse phase HPLC chromatogram of toxins eluted from a Co[0015] ²⁺ affinity column in the presence (top) or absence (bottom) of the voltage sensor domain. B) VSTX1, eluted at the position marked with an arrow (in FIG. 3A), binds to the domain and inhibits KvAP channel currents elicited by a +100 mV depolarization.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based on the surprising discovery by the inventors that a protein comprising a voltage sensor domain of a voltage-dependent ion channel protein retains its native structure, even when immobilized on a solid support. Such a protein is herein referred to as a screening protein. The ion selectively is retained after reconstitution of the full-length channel protein into planar lipid bilayers. [0016]
In one embodiment, the invention relates to a composition of matter suitable for use in screening chemical compounds in order to identify drug candidates that bind to voltage-dependent ion channel proteins. The composition comprises a protein immobilized on a solid support. The protein may contain additional components often found on proteins, such as glycosylation units. [0017]
Voltage-dependent ion channel proteins are selective for particular ions. Such ions include, for example, potassium, sodium, and calcium. Thus, the ion channel protein can be a potassium ion channel protein, a sodium ion channel protein, or a calcium ion channel protein. [0018]
The amino acid sequence of a voltage-dependent ion channel protein across species is highly conserved. Thus, the ion channel protein can be from an organism of any species. [0019]
For example, the amino acid sequence homology for voltage-dependent potassium channel proteins of [0020] Aeropyrum pernix, Pseudomonas aeruginosa, Deinococcus radiodurans, Drosophila melanogaster, Rattus norvegicus and Homo sapiens is compared in FIG. 1. These amino acid sequence were predicted from the corresponding nucleic acid sequences disclosed in Genbank. The accession numbers are given in the brief description of FIG. 1 above.
The Genbank accession numbers of nucleic acid sequences that encode some calcium and sodium channel proteins, as well as some additional potassium channel proteins, are listed below. [0021]
Some examples of Genbank Accession numbers for voltage-dependent calcium channels include [0022] Rattus norvegicus calcium channel, voltage-dependent, T type, alpha 1G subunit, mRNA, Genbank Accession number GI:24429575; Homo sapienscalcium channel, voltage-dependent, alpha 1I subunit(CACNA1I) mRNA, Genbank Accession number GI:21361076; Musmusculus calcium channel, voltage-dependent, L type, alpha 1C subunit (Cacna1c), mRNA, Genbank Accession number GI:6753227; Homo sapiens calcium channel, voltage-dependent, alpha 1G subunit (CACNA1G), mRNA, Genbank Accession number GI:20070162; and Caenorhabditis elegans calcium Channel, Alpha subunit CCA-1 (210.2 kD) (cca-1) mRNA, Genbank Accession number GI:25146600.
Some examples of Genbank Accession numbers for voltage-dependent sodium channels include [0023] Rattus norvegicus sodium channel, voltage-gated, type 11, alpha polypeptide (Scn11a), mRN, Genbank Accession number GI:15011860; Homo sapiens sodium channel, voltage-gated, type I, alpha polypeptide (SCN1A), mRNA, Genbank Accession number GI:21914835; Rattus norvegicus sodium channel, voltage-gated, type 8, alpha polypeptide (Scn8a), mRNA, Genbank Accession number GI:9507066; Mus musculus sodium channel, voltage-gated, type XI, alpha polypeptide (Scn11a), mRNA, Genbank Accession number GI:6755405; and Bos taurus mRNA for voltage-gated sodium channel alpha subunit, Genbank Accession number GI: 18477464.
Some examples of Genbank Accession numbers for voltage-dependent potassium channels include [0024] D. melanogaster ShB1 mRNA for Shaker gene, Genbank Accession number GI:288441; Homo sapiens potassium voltage-gated channel, Shab-related subfamily, member 1 (KCNB1), mRNA, Genbank Accession number GI:27436972; Oryctolagus cuniculus voltage-gated potassium channel Kv2.1 (KCNB1) mRNA, complete cds, Genbank Accession number GI:8572238; Xenopus laevis Kv3.1 potassium channel mRNA, complete cds, Genbank Accession number GI:5817539; and Xenopus laevis maxi-K potassium channel alpha subunit Slo mRNA, complete cds, Genbank Accession number GI:14582151.
All the sequences- corresponding to the above listed Genbank Accession numbers are hereby incorporated by reference. [0025]
For example, the species can be a prokaryotic organism. Some examples of prokaryotic organisms include archaebacteria and bacteria. An example of an archaebacteria is [0026] Aeropyrum pernix. Examples of bacteria include Pseudomonas aeruginosa and Deinococcus radiodurans. Preferably, the ion channel protein is an Aeropyrum pernix (Apernix) ion channel protein, such as KvAP. The amino acid sequence of Apernix KvAP is shown in FIG. 1.
Alternatively, the species can be a eukaryotic organism. Examples of eukaryotic organisms include invertebrates, vertebrates, and mammals. Examples of invertebrates include insects, such as [0027] Drosophila melanogaster, and mollusks. Examples of vertebrates include mammals, reptiles, and fish. Mammals include, for example, dogs, cats, horses, sheep, cows, rats, such as Rattus norvegicus, mice, and primates, including humans (i.e., Homo sapiens). The preferred eukaryotic ion channel protein is a Homo sapien ion channel protein.
The screening protein useful in the present invention can comprise the entire ion channel protein, e.g., the voltage sensor segments, S[0028] 1-S4, and the ion-selective pore segments, S5-S6, including the selectivity filter, i.e. the signature sequence amino acids between P and S6. Preferably, the screening protein includes only the ion channel voltage sensor domain, e.g., segments S1-S4, and excludes an ion conduction pore, e.g., segments S5-S6, including P. See FIGS. 1 and 2.
In a more preferred embodiment, the screening protein comprises an amino acid sequence that consists essentially of the voltage sensor domain, i.e., includes segments S[0029] 1 -S4, and one or more amino acid residues that do not change the essential nature of the voltage sensor domain. The number of amino acid residues is preferably relatively small. In order to constitute a relatively small number of amino acids, the number of amino acid residues should not exceed approximately 100, preferably approximately 50, and more preferably approximately 10 amino acid residues. The additional amino acid residues may, for example, be relics of the method of isolating the voltage sensor domains
In addition, one or more amino acid residues may be added to the screening protein for a specific purpose. For example, amino acids may be added for the purpose of labeling the screening protein or for attachment of the screening protein to a solid support. Examples of an amino acid sequence for attaching screening proteins to a solid support include hexahistidine (e.g., Co[0030] ²⁺ column) and glutathione S-transferase.
The optional amino acids can be attached anywhere on the screening protein. Preferably, the optional amino acids are attached to either the N-terminus or C-terminus. The optional amino acids may also be added to any internal residue in the sequence of the screening protein, as long as the optional amino acids do not disrupt the native structure of the screening protein. [0031]
The screening protein can be a monomer or a polymer. Examples of polymers include dimers, trimers, tetramers, etc. There is no limit to the number of subunits that can polymerize, although screening proteins are typically not larger than tetramers. [0032]
The screening protein can be a functional analog of a naturally occurring voltage-dependent ion channel protein. An analog can, for example, be a substitution or deletion mutant of the ion channel protein. Substitutions and deletions can be made as long as the screening protein continues to satisfy the function of the voltage-dependent ion channel protein described herein. [0033]
Preferably, any substitutions of amino acids in a screening protein are conservative, i.e., within a group of amino acids having similar physicochemical characteristics. Amino acids may be grouped according to their physicochemical characteristics as follows: [0034]
(a) Non-polar amino acids: Ala(A) Ser(S) Thr(T) Pro(P) Gly(G); [0035]
(b) Acidic amino acids: Asn(N) Asp(D) Glu(E) Gln(Q); [0036]
(c) Basic amino acids: His(H) Arg(R) Lys(K); [0037]
(d) Hydrophobic amino acids: Met(M) Leu(L) Ile(I) Val(V); and [0038]
(e) Aromatic amino acids: Phe(F) Tyr(Y) Trp(W). [0039]
During expression, the first five N-terminal amino acids may be replaced by a single leucine residue. Therefore, a screening protein where the first five N-terminal amino acids are replaced by a single leucine residue is considered to be a functional analog. [0040]
In one embodiment, the screening protein is immobilized on a solid support. The screening protein may be attached to the solid support by any method known in the art, and by any type of bond. The bond can be a covalent bond or a non-covalent bond. An example of a non-covalent bond is a hydrogen bond. [0041]
The solid support can be any support that is capable of immobilizing the screening protein. Examples of solid supports include a resin, a microtitre plate, and nitrocellulose paper. The resin may, for example, comprise cobalt, nickel, nickel-NTA agarose, and glutathione sepharose. [0042]
In another embodiment, the invention relates to a labeled screening protein suitable for use in identifying chemical compounds that bind to voltage-dependent ion channel proteins. The labeled screening protein comprises an ion channel voltage sensor domain of the ion channel protein and a detectable label. The screening protein may be any of the screening proteins described herein. Methods for preparing a labeled screening protein are described below. [0043]
The label may be radioactive. Some examples of useful radioactive labels include [0044] ³²p, ¹²⁵I, ¹³¹I, ³⁵S, ¹⁴C, and ³H. Use of radioactive labels have been described in U.K. 2,034,323, U.S. Pat. No. 4,358,535, and U.S. Pat. No. 4,302,204.
Some examples of non-radioactive labels include enzymes and chromophores. Useful enzymatic labels include enzymes that cause a detectable change in a substrate. Some useful enzymes and their substrates include, for example, horseradish peroxidase (pyrogallol and o-phenylenediamine), beta-galactosidase (fluorescein beta-D-galactopyranoside), and alkaline phosphatase (5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium). The use of enzymatic labels have been described in U.K. 2,019,404, EP 63,879, in Ausubel, F. M. et al. (Eds.), Rotman 1961[0045] . Proc. Natl. Acad. Sci. USA 47:1981-1991, and by Current Protocols in Molecular Biology, John Wiley & Sons, Inc., New York (1999).
Useful chromophores include, for example, fluorescent, chcmiluminescent, and bioluminescent molecules, as well as dyes. Some specific chromophores useful in the present invention include, for example, fluorescein, rhodamine, Texas red, phycoerythrin, umbelliferone, luminol. [0046]
In another embodiment, the invention relates to a kit suitable for use in identifying chemical compounds that bind to voltage-dependent ion channel proteins. The kit comprises a screening protein that comprises an ion channel voltage sensor domain of the ion channel protein and a solid support. The screening protein can comprise any screening protein described herein. The solid support present in the kit can be any support described herein. [0047]
The kit may further contain optional components that are helpful in preparing reagents and carrying out procedures described herein. Some examples of optional components include labels, nucleases, proteases, buffers, etc. [0048]
In another embodiment, the invention relates to a method for screening for drug candidates that target voltage-dependent ion channels. The first step in the method is providing a screening protein. Methods for preparing screening proteins by expression of the DNA encoding a screening protein in a host cell are described below. [0049]
The screening protein is contacted with a chemical compound. The chemical compound can be any molecule. Examples of molecules include biological molecules and small molecules. The chemical compounds can be a mixture of one or more different chemical compounds. [0050]
A biological molecule is any molecule which contains a polyamino acid, a polynucleotide, or a polysaccharide, and has a molecular weight greater than 450. Polyamino acids include proteins, polypeptides, and peptides. [0051]
Small molecules are typically organic compounds, including organometallic and organosilicon compounds, and the like, and generally have molecular weights of approximately 450 or less. Small molecules can further include molecules that would otherwise be considered biological molecules, except their molecular weight is not greater than 450. Thus, small molecules can include, monosaccharides, oligosaccharides, amino acids, oligopeptides, nucleotides, oligonucleotides, and their derivates, having a molecular weight of 450 or less. [0052]
It is emphasized that a small molecule can have any molecular weight. They are merely called small molecules because they typically have molecular weights less than 450. [0053]
The screening protein can be contacted with the chemical compound by any method known to those in the art. Preferably, either the screening protein or the chemical compound is immobilized on a solid support. [0054]
For example, the screening protein may be immobilized on a resin. The screening protein can be contacted with the chemical compound by cluting the chemical compound through a column containing the screening protein immobilized on the resin. [0055]
Alternatively, the chemical compound may be immobilized on a microtitre plate. The screening proteins can be contacted with the chemical compound by incubating the plate with the chemical compound. Many chemical compounds may be immobilized on a plate, thereby allowing the rapid screening of the compounds. [0056]
The next step in screening is to determine whether the chemical compound binds to the screening proteins. Binding can be determined by any method known in the art. [0057]
For example, a label may be bound to the chemical compound or to the screening protein, depending on which is immobilized to the solid support. Usually, the component that is not immobilized is the component that is labeled. Thus, if the screening protein is immobilized, the chemical compound is labeled. If the chemical compound is immobilized, the screening protein is labeled. [0058]
After contacting the chemical compounds and the screening proteins as described above, detection of an immobilized label indicates the binding of screening proteins to a chemical compound. Such chemical compounds are drug candidates that target voltage dependent ion channel proteins. [0059]
Preferably, the drug candidate alters the function of the voltage dependent ion channel proteins, typically by causing the ion channel proteins either to stay open or to stay closed. For example, a drug candidate that causes the ion channel protein to stay closed inhibits the ion channel proteins. Any assay known to those in the art can be used to determine whether a drug candidate alters voltage dependent ion channels. An example of an assay is an electrophysological assay described in, for instance, Example 2, see below. [0060]
Electrical activity, (i.e., cellular electrical activity), whether normal or abberant, is generated by voltage dependent ion channels, and therefore can be influenced by agents that affect voltage dependent ion channels. The drug candidate may be useful for treating any condition mediated by aberrant electrical activity, such as the magnitude of the resting membrane voltage, or shape and frequency of the action potential. [0061]
The condition can be, for example, asthma, hypertension, arrhythmia, epilepsy, nerve conduction abnormalities, atrial fibrillation, conditions associated with immune abnormalities due to, for instance, inappropriate lymphocyte stimulation, conditions associated with abnormalities of fluid and/or electrolyte secretion by, for example, epithelial membranes, such as in cystic fibrosis, and conditions associated with abnormal excretion by the renal system, such as in certain nephropathies, etc. Aberrant electrical activity can also initiate uptake or release of neurotransmitters, or initiate contraction of muscles. [0062]
The aberrant electrical activity can occur in any cell, organ or system in a body. Examples of cells include nerve cells, such as neurons, glial cell, and dendrites. Examples of organs and systems include heart, brain, lung, kidney, liver, muscle, digestive system, and peripheral nervous system. The muscle can be cardiac, skeletal, or smooth muscle. [0063]
The neurotransmitter can be any neurotransmitter. Examples of neurotransmitters include dopamine, epinephrine and norepinephrine. [0064]
Neurotransmitters are generally either excitatory neurotransmitters or inhibitory neurotransmitters. Excitatory neurotransmitter typically open cation channels, causing an influx of, for example, sodium, which depolarizes the postsynaptic membrane for firing an action potential. Examples of excitatory neurotransmitters include acetylcholine, glutamate, and serotonin. [0065]
Alternatively, inhibitory neurotransmitters usually suppresses firing of an action potential by keeping postsynaptic membranes polarized. Examples of inhibitory neurotransmitters include γ-aminobutyric acid and glycine. [0066]
These candidate drugs can be further tested for activity against a condition mediated by an aberrant electrical activity by methods known to those in the art. For example, the further testing can be those that are routinely done by clinicians and physicians during pre-clinical and clinical trials. [0067]
General Methods and Assays [0068]
The screening proteins may be prepared by methods that are well known in the art. Some general methods and techniques are described below. More specific methods and techniques are found in the specific examples below. [0069]
One method for producing screening proteins includes isolating or synthesizing DNA encoding the screening protein, and producing the recombinant protein by expressing the DNA, optionally in a recombinant vector, in a suitable host cell. [0070]
The proteins may also be made synthetically, i.e. from individual amino acids, or semisynthetically, i.e. from oligopeptide units or a combination of oligopeptide units and individual amino acids. Suitable methods for synthesizing proteins are described by Stuart and Young in “Solid Phase Peptide Synthesis,” Second Edition, Pierce Chemical Company (1984), Solid Phase Peptide Synthesis, Methods Enzymol., 289, Academic Press, Inc, New York (1997). [0071]
Nucleic acids encoding the proteins may also be synthesized in vitro. Suitable methods for synthesizing DNA are described by Caruthers et al. 1985[0072] . Science 230:281-285 and DNA Structure, Part A: Synthesis and Physical Analysis of DNA, Lilley, D. M. J. and Dahlberg, J. E. (Eds.), Methods Enzymol., 211, Academic Press, Inc., New York (1992).
Nucleic acid molecules encoding the ion channel proteins may be designed or assembled from known nucleic acid sequences encoding the ion channel proteins. The nucleic acid sequences may be obtained by those skilled in the art from collections of nucleic acid sequences, such as GenBank. [0073]
Alternatively, the nucleic acid sequence may be derived from a known amino acid sequence of an ion channel protein using the genetic code, as is routine to those of skill in the art. The nucleic acid sequence may then be synthesized as described above. Similarly, the amino acid sequences of the screening proteins may be derived from the corresponding nucleic acid sequence. [0074]
The methods, constructs and host cells suitable for production of screening proteins in standard small-scale culture systems, as well as large-scale production systems, include fermenter systems, hollow fiber culture systems, tumbler systems, and suspension culture systems to name but a few. [0075]
Methods and procedures for the manipulation of nucleic acids, polymerase chain reaction (PCR) methods for amplification of nucleic acids, construction of expression vectors, transformation of host cells, and the culture of transformed cells for the production of protein are known. These and many more relevant methods may be found in a variety of laboratory manuals, texts and guides. For a general guide, see, for instance, Sambrook & Russel, (2001) Molecular Cloning, Third edition, Cold Spring Harbor Press. Other useful sources include: Ausubel et al., 1992 Short Protocols in Molecular Biology, Second edition, John Wiley & Son; Gene Expression Technology, Methods in Enzymology Vol. 185 (ed. David Goeddel et al., Academic Press, Inc., London, 1991); Gene Structure and Expression, Second Edition, J. D. Hawkins (Cambridge University Press, London, 1991); PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990, Academic Press, San Diego, Calif.); Methods in Molecular Biology (Vol. 7), Gene Transfer and Expression Protocols, (ed. E. J. Murray, 1991, The Humana Press Inc., Clifton, N.J.). [0076]
The nucleic acid encoding screening proteins may be replicated and expressed in a suitable host cell. Suitable host cells include prokaryotic host cells and eukaryotic host cells. Suitable prokaryotic host cells include [0077] E. coli cells which are preferred. Suitable eukaryotic host cells include yeast cells, insect cells and mammalian cells, the latter being preferred.
Screening proteins are expressed in eukaryotic hosts in preference to prokaryotic hosts in cases where the protein must be post-transcriptionally modified. Examples of post-transcriptional modification include glycosylation, phosphorylation, disulfide bond formation, oligomerization and specific cleavage of the transcribed protein product. [0078]
Prokaryotic hosts do not perform certain post-transcriptional modifications of ion channel proteins, such as for instance glycosylation. For this reason expression in eukaryotic systems is preferred despite the higher costs associated with production of biologics in eukaryotic systems as compared with the costs of biologics produced in prokaryotic host systems. [0079]
Prokaryotic host systems are preferred for expression and production of screening proteins of the invention that do not require post-transcriptional modifications that are unique to eukaryotic systems and where the screening proteins are correctly folded or may be refolded in vitro. [0080]
Many standard well known cloning and expression and isolation/purification techniques that reflect the state of the art in recombinant DNA and protein methods are described in detail in Sambrook & Russel, [0081] Molecular Cloning: A Laboratory Manual, Third Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2001). Techniques for expression of cloned genes in E. coli and in mammalian cells is described in detail in Chapters 15 and 16-17, respectively of the Sambrook & Russel Laboratory Manual (Id).
Labels [0082]
The labels may be conjugated to the screening protein or chemical compound by methods that are well known in the art. The labels may be directly attached through a functional group on the screening protein or chemical compound. The screening protein or chemical compound either contains or can be caused to contain such a functional group. Some examples of suitable functional groups include, for example, amino, carboxyl, sulfhydryl, maleimide, isocyanate, isothiocyanate. [0083]
Alternatively, labels such as enzymes and chromophoric molecules may be conjugated to the screening protein or chemical compound by means of coupling agents, such as dialdehydes, carbodiimides, dimaleimides, and the like. [0084]

EXAMPLES

Example 1

Preparation of Aeropyrum pernix KvAP

A sample of [0085] Aeropyrum pernix was obtained from the Japan Collection of Microorganisms. Aeropyrum pernix cultures were grown in a solution of autoclaved sea water supplemented with bactoyeast extract, trypticase peptone and sodium thiosulphate for three days in an oil bath maintained at 95° C.
[0086] Aeropyrum pernix genomic DNA was collected by standard procedures. The gene coding for KvAP starting from methionine 14 was cloned by polymerase chain reaction (PCR) amplification of the genomic DNA and inserted into the protein expression vector pQE60 (Qiagen) between NcoI and BglII restriction endonuclease sites with a thrombin cleavage site between a carboxy-terminal hexahistidine sequence and the channel.
Channel protein was expressed in XL 1-blue cell cultures grown in LB medium supplemented with 10 mM BaCl2 on induction with 0.4 mM isopropyl-b-D-thiogalactopyranoside (IPTG). Expressed protein was extracted with 40 mM decylmaltoside (DM) and purified on a Talon Co[0087] ²⁺ affinity column (Clontech).
The protein was maintained in 5 mM DM, 20 mM Tris, pH 8.0, and 100 mM KCl. Nonspecifically bound protein was washed using 15 mM imidazole added to the above buffer, and the channel then eluted with 400 mM imidazole. Immediately after elution, 1.0 unit of thrombin (Roche) per 3.0 mg channel was added to cleave the hexahistidine sequence overnight at room temperature. Protein was concentrated to about 15 mg ml[0088] ⁻¹and run on a Superdex-200 (10/30) column (Pharmacia) in the above buffer.
MALDI-TOF mass spectrometry (PerSeptive Biosystems Voyager-STR) and N-terminal sequencing analysis (Rockefeller University Protein/DNA Technology Center) indicated that the KvAP protein undergoes a modification during expression in which the first five residues of the encoded construct are replaced with a single leucine residue in the expressed channel protein. [0089]

Example 2

KvAP of Prokaryotic Organism, Aeropyrum pernix, is Functionally Similar to Eukaryotic Kv Channels

KvAP channels were expressed in [0090] Escherichia coli, extracted with decylmaltoside, purified and reconstituted into planar lipid bilayers of 1-palmitoyl-2-oleoyl-phosphotidylglycerol (POPG) and 1-palmitoyl-2-oleoyl-phosphotidylethanolamine (POPE) for functional studies.
KvAP channels have a large conductance—the slope of the single-channel current-voltage relationship recorded in solutions containing 150 mM KCl and 10 mM HEPES, pH 7.0, on both sides of the membrane shows a conductance of approximately 170 pS. The presence of the K[0091] ⁺ channel signature sequence indicates that the KvAP pore should be strongly selective for K⁺ versus Na⁺ ions.
To examine ion selectivity, the reversal potential of macroscopic tail currents in a tenfold K[0092] ⁺ gradient by substituting 135 mM NaCl for 135 mM KCl in the solution on one side of the membrane. The measured reversal potential is −56.5±1.2 mV, which is near the Nernst potential for a perfectly K⁺ selective pore at room temperature (21° C.).

Example 3

KvAP of Prokaryotic Organism, Aeropyrum pernix, is Structurally Similar to Eukaryotic Kv Channels

To examine the structural similarity of KvAP to eukaryotic K[0093] ⁺ channel pores, the ability of a small protein toxin from scorpion venom to inhibit the KvAP channel was examined.
Venomous animals, such as scorpions, exploit the conservation of ion-channel structure by producing a toxin that recognizes a structural feature common to an entire family of ion channels. By making many sequence variants of the same basic toxin structure, a scorpion can inhibit virtually every member of an ion channel family. The scorpion [0094] Leiurus quinquestriatus hebraeus specializes in a family of pore-blocking toxins, exemplified by charybdotoxin (CTX), which fit, like a key to a lock, to the pore entryway of K⁺ channels.
CTX inhibits the KvAP channel with a dissociation constant (Kd) of about 0.4 mM. We emphasize that CTX would not bind to the KvAP channel if its pore were not very similar in structure to that of eukaryotic K[0095] ⁺ channels.

Example 4

Voltage-Dependence of KvAP is Similar to Eukaryotic Kv Channels.

To determine the orientation of channels incorporated into planar lipid bilayers, we used CTX, which causes inhibition by binding only to the extracellular side. KvAP channels open in response to membrane depolarization (e.g., when the voltage of the CTX-insensitive (intracellular) side of the membrane is made positive relative to the CTX-sensitive (extracellular) side. KvAP channels are strongly voltage-dependent, opening as a function of membrane voltage, similar to Shaker and other eukaryotic neuronal Kv channels. [0096]

Example 5

Isolation of KvAP Voltage Sensor (S 1-S4).

DNA for the isolated voltage sensor (from KvAP) encoding Met1 to Lys147 was cloned into a pQE60 expression vector (Qiagen) between NcoI and BglII sites with a thrombin cleavage site followed by a C-terminal hexahistadine sequence. [0097]
Protein was expressed in [0098] E. coli XL1-Blue cells by induction (at A₆₀₀˜1.0) with 0.4 mM isopropyl-β-D-thiogalactopyranoside (IPTG) for 4 hours at 37° C. Cells were harvested and lysed in 50 mM Tris, pH 8.0, 100 mM KCl, containing 1 μg ml⁻¹Leupeptin, 1 μg ml⁻¹Pepstatin, 2 μg ml⁻¹Aprotinin and 1mM PMSF (Sigma) to inhibit proteases.
Protein was then extracted from the cell lysate for 3 hours at room temperature in the above solution by adding 40 mM decylmaltoside (DM). The extracted cell lysate was centrifuged at 16,000 rpm for 20 minutes and the supernatant was collected and loaded onto a Talon Co[0099] ²⁺ affinity column (Clontech) equilibrated in 5 mM DM, 20 mM Tris, pH 8.0, and 100 mM KCl. Nonspecifically bound protein was washed using 10 mM imidazole added to the above buffer, and the voltage sensor domain was eluted with 300 to 400 mM imidazole in the above buffer. The isolated voltage sensor domain was then dialyzed against 100 ml of the above buffer for ˜7-8 hours and transferred to 100 ml of fresh buffer for dialysis overnight. Voltage sensor domain was concentrated to ˜5 mg ml⁻¹, calculated by 280 nm absorbance using the extinction coefficient ε=1.01 (mg ml⁻¹*cm)⁻¹determined from amino acid analysis. Purification yields ˜3 mg of voltage sensor domain protein per liter of bacterial culture.
Analysis by MALDI-TOF mass spectrometry (PerSeptive Biosystems Voyager-STR) and N-terminal sequencing indicated that the N-terminus undergoes modification during expression in which the first five residues of the encoded constructs are replaced with a single leucine residue. [0100]

Example 6

Isolated Voltage Sensor Domain Retains Native Structure and Isolates and Binds to Toxins.

Isolated voltage sensor was expressed and purified according to Example 5. To generate the voltage sensor domain column for isolation of toxins, 0.1 ml of Co[0101] ²⁺ resin was washed with water and then equilibrated with Buffer A (20 mM Tris pH 8.0, 100 mM KCl, and 10 mM DM) in an eppendorf tube by 3-4 rounds of centrifugation (500 rpm) to collect resin, careful removal of the supernatant with a pipette and resuspension of the resin in either 1 ml of water or 0.4 ml of Buffer A.
Approximately 2 mg of voltage sensor domain was added to the equilibrated resin. The resin and voltage sensor domain protein were incubated for ˜15 minutes. The resin was then applied to a micro chromatography column (Biorad). Samples of the voltage sensor domain prior to addition to the resin and the flow through after addition of resin to the column was kept and later run on an SDS gel to ensure that an excess of protein has been added to the resin and saturated with protein. [0102]
The column was washed twice with 2 column volumes of Buffer A to remove any remaining unbound voltage sensor domain protein. A control column was prepared containing 0.1 ml of resin treated equivalently with the exception that instead of adding voltage sensor domain protein to the equilibrated resin, the same volume of Buffer A was added. [0103]
Venom from [0104] Grammostola spatulata (SpiderPharm) was diluted ten fold in Buffer A and 0.1 ml of the venom stock was applied to the column with bound S1-S4 domain or the control column. Both columns were washed to minimize non-specifically bound toxins, first in 4 column volumes Buffer A and then 4 column volumes Buffer A with 10 mM imidazole.
Remaining protein was eluted from both columns with 0.1 ml of Buffer A containing 400 mM imidazole and reduced with 50 mM DTT at 37° C. for 2 hours to improve separation by reverse phase high performance liquid chromatography (HPLC). Equal volumes of eluted, reduced protein from the two columns were run on an Agilent 1100 Series HPLC with a C-18 reverse-phase 5μm 80å column using a 2 min isocratic flow of 75% mobile phase A (H[0105] ₂0, 0.1% TFA) and 25% mobile phase B (90% acetonitrile, 10% H₂0, 0.1% TFA) followed by a 25%-55% mobile phase B gradient over 40 minutes. Peaks are collected and analyzed by MALDI-TOF mass spectrometry focusing on the low molecular weight range (˜800-10,000 Da).
The isolate voltage sensor immobilized to a resin in the column efficiently purifies toxins from tarantula venom (FIG. 3A). These toxins also inhibit functional KvAP channels in an electrophysiological assay (FIG. 3B). [0106]
Thus, the data show that the isolated voltage sensor retains native structure due to binding of protein toxins with high affinity to the voltage sensor. [0107]
These experiments were performed with voltage-dependent ion channels from [0108] Aeropyrum pernix. However, due to the close homology between the amino acid sequences of voltage-dependent ion channels across species, the present invention can be applied to voltage sensor domains from any species, including Homo sapiens.
1 21 1 295 PRT Aeropyrum pernix 1 Met Ser Val Glu Arg Trp Val Phe Pro Gly Cys Ser Val Met Ala Arg 1 5 10 15 Phe Arg Arg Gly Leu Ser Asp Leu Gly Gly Arg Val Arg Asn Ile Gly 20 25 30 Asp Val Met Glu His Pro Leu Val Glu Leu Gly Val Ser Tyr Ala Ala 35 40 45 Leu Leu Ser Val Ile Val Val Val Val Glu Tyr Thr Met Gln Leu Ser 50 55 60 Gly Glu Tyr Leu Val Arg Leu Tyr Leu Val Asp Leu Ile Leu Val Ile 65 70 75 80 Ile Leu Trp Ala Asp Tyr Ala Tyr Arg Ala Tyr Lys Ser Gly Asp Pro 85 90 95 Ala Gly Tyr Val Lys Lys Thr Leu Tyr Glu Ile Pro Ala Leu Val Pro 100 105 110 Ala Gly Leu Leu Ala Leu Ile Glu Gly His Leu Ala Gly Leu Gly Leu 115 120 125 Phe Arg Leu Val Arg Leu Leu Arg Phe Leu Arg Ile Leu Leu Ile Ile 130 135 140 Ser Arg Gly Ser Lys Phe Leu Ser Ala Ile Ala Asp Ala Ala Asp Lys 145 150 155 160 Ile Arg Phe Tyr His Leu Phe Gly Ala Val Met Leu Thr Val Leu Tyr 165 170 175 Gly Ala Phe Ala Ile Tyr Ile Val Glu Tyr Pro Asp Pro Asn Ser Ser 180 185 190 Ile Lys Ser Val Phe Asp Ala Leu Trp Trp Ala Val Val Thr Ala Thr 195 200 205 Thr Val Gly Tyr Gly Asp Val Val Pro Ala Thr Pro Ile Gly Lys Val 210 215 220 Ile Gly Ile Ala Val Met Leu Thr Gly Ile Ser Ala Leu Thr Leu Leu 225 230 235 240 Ile Gly Thr Val Ser Asn Met Phe Gln Lys Ile Leu Val Gly Glu Pro 245 250 255 Glu Pro Ser Cys Ser Pro Ala Lys Leu Ala Glu Met Val Ser Ser Met 260 265 270 Ser Glu Glu Glu Phe Glu Glu Phe Val Arg Thr Leu Lys Asn Leu Arg 275 280 285 Arg Leu Glu Asn Ser Met Lys 290 295 2 283 PRT Pseudomonas aeruginosa 2 Met Ser Ala Pro Asp Ser Trp Arg Glu Arg Leu Tyr Ile Val Ile Phe 1 5 10 15 Gln Thr Asp Thr Arg Asp Gly Arg Arg Phe Asp Ser Ala Leu Leu Leu 20 25 30 Val Ile Leu Ala Ser Leu Leu Val Val Met Ile Asp Ser Ile Asp Glu 35 40 45 Ile His Gln Asp Tyr Gly Asp Leu Leu Ala Tyr Ile Glu Trp Gly Phe 50 55 60 Thr Gly Ile Phe Leu Val Glu Tyr Leu Leu Arg Leu Tyr Cys Ser Pro 65 70 75 80 Lys Pro Leu Arg Tyr Ala Phe Ser Phe Tyr Gly Leu Val Asp Leu Leu 85 90 95 Ala Ile Leu Pro Gly Phe Leu Ala Leu Leu Tyr Pro Asp Ala Gln Tyr 100 105 110 Leu Leu Ile Val Arg Val Ile Arg Met Leu Arg Ile Phe Arg Val Leu 115 120 125 Lys Leu Arg Gln Tyr Leu Ser Gln Ala Asn Phe Leu Leu Thr Ala Leu 130 135 140 Arg Gly Ser Lys Gln Lys Ile Ile Val Phe Phe Leu Thr Val Met Thr 145 150 155 160 Leu Val Thr Val Phe Gly Ala Leu Met Tyr Val Val Glu Gly Pro Glu 165 170 175 His Gly Phe Thr Ser Ile Pro Arg Gly Ile Tyr Trp Ala Ile Val Thr 180 185 190 Leu Thr Thr Val Gly Phe Gly Asp Ile Thr Pro Lys Thr Pro Leu Gly 195 200 205 Gln Ala Ile Ala Ser Leu Val Met Leu Thr Gly Tyr Ser Ile Ile Ala 210 215 220 Val Pro Thr Gly Ile Phe Thr Ala Glu Leu Ala Thr Ala Met Arg Gln 225 230 235 240 Asp Pro Ala Asn Leu Leu Gln Arg Asp Cys Pro Val Cys Arg Lys Ala 245 250 255 Thr His Glu Val Gln Ala Ala Phe Cys Cys Arg Cys Gly Asn Pro Leu 260 265 270 Phe Pro Arg Glu Glu Gly Ser His Gly Lys Ser 275 280 3 280 PRT Deinococcus radiodurans 3 Met Ile Ser Pro Pro Pro Asp Pro Pro His Pro Asp His Arg Pro Pro 1 5 10 15 Trp Arg Arg Trp Leu Gly Asn Leu Ile Phe Gly Leu Ser Thr Pro Ala 20 25 30 Ala Arg Ala Tyr Asp Lys Ile Val Ile Val Leu Ile Val Ala Ser Val 35 40 45 Leu Ala Val Thr Leu Glu Ser Val Pro Glu Leu Ser His Ala Val Arg 50 55 60 Ala Arg Leu Arg Gln Thr Glu Trp Val Phe Thr Val Met Phe Thr Ala 65 70 75 80 Asp Tyr Leu Leu Arg Leu Leu Gly Ala Arg Arg Pro Leu Arg Tyr Ala 85 90 95 Leu Ser Phe Tyr Gly Leu Val Asp Leu Leu Thr Ile Leu Pro Ser Tyr 100 105 110 Leu Ser Leu Leu Phe Pro Gly Thr Gln Tyr Leu Leu Val Val Arg Ala 115 120 125 Leu Arg Leu Leu Arg Val Phe Arg Val Phe Lys Leu Ala Arg Tyr Ser 130 135 140 Asp Gln Ala Ala Leu Ile Gly Glu Ala Leu Gln Ala Ser Arg Glu Lys 145 150 155 160 Ile Ile Val Phe Phe Ile Ser Val Leu Ser Met Val Ile Val Phe Gly 165 170 175 Thr Leu Leu Tyr Met Val Glu Gly Pro Glu Ser Gly Phe Thr Ser Ile 180 185 190 Pro Thr Ser Ile Tyr Trp Ala Val Val Thr Val Thr Thr Val Gly Tyr 195 200 205 Gly Asp Ile Ser Pro Lys Thr Gly Leu Gly Lys Phe Ile Ala Thr Leu 210 215 220 Ala Met Leu Ser Gly Tyr Ala Ile Ile Ala Val Pro Thr Gly Ile Val 225 230 235 240 Thr Val Gly Leu Gln Gln Ala Gln Glu Ala Arg Arg Gly Arg Thr Cys 245 250 255 Pro Gln Cys Gly Leu Ser Arg His Asp Ala Asp Ala Arg Phe Cys Lys 260 265 270 Arg Cys Gly Glu Asn Leu Pro Gly 275 280 4 656 PRT Drosophila melanogaster 4 Met Ala Ala Val Ala Gly Leu Tyr Gly Leu Gly Glu Asp Arg Gln His 1 5 10 15 Arg Lys Lys Gln Gln Gln Gln Gln Gln His Gln Lys Glu Gln Leu Glu 20 25 30 Gln Lys Glu Glu Gln Lys Lys Ile Ala Glu Arg Lys Leu Gln Leu Arg 35 40 45 Glu Gln Gln Leu Gln Arg Asn Ser Leu Asp Gly Tyr Gly Ser Leu Pro 50 55 60 Lys Leu Ser Ser Gln Asp Glu Glu Gly Gly Ala Gly His Gly Phe Gly 65 70 75 80 Gly Gly Pro Gln His Phe Glu Pro Ile Pro His Asp His Asp Phe Cys 85 90 95 Glu Arg Val Val Ile Asn Val Ser Gly Leu Arg Phe Glu Thr Gln Leu 100 105 110 Arg Thr Leu Asn Gln Phe Pro Asp Thr Leu Leu Gly Asp Pro Ala Arg 115 120 125 Arg Leu Arg Tyr Phe Asp Pro Leu Arg Asn Glu Tyr Phe Phe Asp Arg 130 135 140 Ser Arg Pro Ser Phe Asp Ala Ile Leu Tyr Tyr Tyr Gln Ser Gly Gly 145 150 155 160 Arg Leu Arg Arg Pro Val Asn Val Pro Leu Asp Val Phe Ser Glu Glu 165 170 175 Ile Lys Phe Tyr Glu Leu Gly Asp Gln Ala Ile Asn Lys Phe Arg Glu 180 185 190 Asp Glu Gly Phe Ile Lys Glu Glu Glu Arg Pro Leu Pro Asp Asn Glu 195 200 205 Lys Gln Arg Lys Val Trp Leu Leu Phe Glu Tyr Pro Glu Ser Ser Gln 210 215 220 Ala Ala Arg Val Val Ala Ile Ile Ser Val Phe Val Ile Leu Leu Ser 225 230 235 240 Ile Val Ile Phe Cys Leu Glu Thr Leu Pro Glu Phe Lys His Tyr Lys 245 250 255 Val Phe Asn Thr Thr Thr Asn Gly Thr Lys Ile Glu Glu Asp Glu Val 260 265 270 Pro Asp Ile Thr Asp Pro Phe Phe Leu Ile Glu Thr Leu Cys Ile Ile 275 280 285 Trp Phe Thr Phe Glu Leu Thr Val Arg Phe Leu Ala Cys Pro Asn Lys 290 295 300 Leu Asn Phe Cys Arg Asp Val Met Asn Val Ile Asp Ile Ile Ala Ile 305 310 315 320 Ile Pro Tyr Phe Ile Thr Leu Ala Thr Val Val Ala Glu Glu Glu Asp 325 330 335 Thr Leu Asn Leu Pro Lys Ala Pro Val Ser Pro Gln Asp Lys Ser Ser 340 345 350 Asn Gln Ala Met Ser Leu Ala Ile Leu Arg Val Ile Arg Leu Val Arg 355 360 365 Val Phe Arg Ile Phe Lys Leu Ser Arg His Ser Lys Gly Leu Gln Ile 370 375 380 Leu Gly Arg Thr Leu Lys Ala Ser Met Arg Glu Leu Gly Leu Leu Ile 385 390 395 400 Phe Phe Leu Phe Ile Gly Val Val Leu Phe Ser Ser Ala Val Tyr Phe 405 410 415 Ala Glu Ala Gly Ser Glu Asn Ser Phe Phe Lys Ser Ile Pro Asp Ala 420 425 430 Phe Trp Trp Ala Val Val Thr Met Thr Thr Val Gly Tyr Gly Asp Met 435 440 445 Thr Pro Val Gly Val Trp Gly Lys Ile Val Gly Ser Leu Cys Ala Ile 450 455 460 Ala Gly Val Leu Thr Ile Ala Leu Pro Val Pro Val Ile Val Ser Asn 465 470 475 480 Phe Asn Tyr Phe Tyr His Arg Glu Thr Asp Gln Glu Glu Met Gln Ser 485 490 495 Gln Asn Phe Asn His Val Thr Ser Cys Pro Tyr Leu Pro Gly Thr Leu 500 505 510 Gly Gln His Met Lys Lys Ser Ser Leu Ser Glu Ser Ser Ser Asp Met 515 520 525 Met Asp Leu Asp Asp Gly Val Glu Ser Thr Pro Gly Leu Thr Glu Thr 530 535 540 His Pro Gly Arg Ser Ala Val Ala Pro Phe Leu Gly Ala Gln Gln Gln 545 550 555 560 Gln Gln Gln Gln Pro Val Ala Ser Ser Leu Ser Met Ser Ile Asp Lys 565 570 575 Gln Leu Gln His Pro Leu Gln His Val Thr Gln Thr Gln Leu Tyr Gln 580 585 590 Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Asn Gly Phe Lys Gln Gln 595 600 605 Gln Gln Gln Thr Gln Gln Gln Leu Gln Gln Gln Gln Ser His Thr Ile 610 615 620 Asn Ala Ser Ala Ala Ala Ala Thr Ser Gly Ser Gly Ser Ser Gly Leu 625 630 635 640 Thr Met Arg His Asn Asn Ala Leu Ala Val Ser Ile Glu Thr Asp Val 645 650 655 5 857 PRT Rattus norvegicus 5 Met Pro Ala Gly Met Thr Lys His Gly Ser Arg Ser Thr Ser Ser Leu 1 5 10 15 Pro Pro Glu Pro Met Glu Ile Val Arg Ser Lys Ala Cys Ser Arg Arg 20 25 30 Val Arg Leu Asn Val Gly Gly Leu Ala His Glu Val Leu Trp Arg Thr 35 40 45 Leu Asp Arg Leu Pro Arg Thr Arg Leu Gly Lys Leu Arg Asp Cys Asn 50 55 60 Thr His Asp Ser Leu Leu Gln Val Cys Asp Asp Tyr Ser Leu Glu Asp 65 70 75 80 Asn Glu Tyr Phe Phe Asp Arg His Pro Gly Ala Phe Thr Ser Ile Leu 85 90 95 Asn Phe Tyr Arg Thr Gly Arg Leu His Met Met Glu Glu Met Cys Ala 100 105 110 Leu Ser Phe Ser Gln Glu Leu Asp Tyr Trp Gly Ile Asp Glu Ile Tyr 115 120 125 Leu Glu Ser Cys Cys Gln Ala Arg Tyr His Gln Lys Lys Glu Gln Met 130 135 140 Asn Glu Glu Leu Lys Arg Glu Ala Glu Thr Leu Arg Glu Arg Glu Gly 145 150 155 160 Glu Glu Phe Asp Asn Thr Cys Cys Ala Glu Lys Arg Lys Lys Leu Trp 165 170 175 Asp Leu Leu Glu Lys Pro Asn Ser Ser Val Ala Ala Lys Ile Leu Ala 180 185 190 Ile Ile Ser Ile Met Phe Ile Val Leu Ser Thr Ile Ala Leu Ser Leu 195 200 205 Asn Thr Leu Pro Glu Leu Gln Ser Leu Asp Glu Phe Gly Gln Ser Thr 210 215 220 Asp Asn Pro Gln Leu Ala His Val Glu Ala Val Cys Ile Ala Trp Phe 225 230 235 240 Thr Met Glu Tyr Leu Leu Arg Phe Leu Ser Ser Pro Lys Lys Trp Lys 245 250 255 Phe Phe Lys Gly Pro Leu Asn Ala Ile Asp Leu Leu Ala Ile Leu Pro 260 265 270 Tyr Tyr Val Thr Ile Phe Leu Thr Glu Ser Asn Lys Ser Val Leu Gln 275 280 285 Phe Gln Asn Val Arg Arg Val Val Gln Ile Phe Arg Ile Met Arg Ile 290 295 300 Leu Arg Ile Leu Lys Leu Ala Arg His Ser Thr Gly Leu Gln Ser Leu 305 310 315 320 Gly Phe Thr Leu Arg Arg Ser Tyr Asn Glu Leu Gly Leu Leu Ile Leu 325 330 335 Phe Leu Ala Met Gly Ile Met Ile Phe Ser Ser Leu Val Phe Phe Ala 340 345 350 Glu Lys Asp Glu Asp Asp Thr Lys Phe Lys Ser Ile Pro Ala Ser Phe 355 360 365 Trp Trp Ala Thr Ile Thr Met Thr Thr Val Gly Tyr Gly Asp Ile Tyr 370 375 380 Pro Lys Thr Leu Leu Gly Lys Ile Val Gly Gly Leu Cys Cys Ile Ala 385 390 395 400 Gly Val Leu Val Ile Ala Leu Pro Ile Pro Ile Ile Val Asn Asn Phe 405 410 415 Ser Glu Phe Tyr Lys Glu Gln Lys Arg Gln Glu Lys Ala Ile Lys Arg 420 425 430 Arg Glu Ala Leu Glu Arg Ala Lys Arg Asn Gly Ser Ile Val Ser Met 435 440 445 Asn Met Lys Asp Ala Phe Ala Arg Ser Ile Glu Met Met Asp Ile Val 450 455 460 Val Glu Lys Asn Gly Glu Ser Ile Ala Lys Lys Asp Lys Val Gln Asp 465 470 475 480 Asn His Leu Ser Pro Asn Lys Trp Lys Trp Thr Lys Arg Ala Leu Ser 485 490 495 Glu Thr Ser Ser Ser Lys Ser Phe Glu Thr Lys Glu Gln Gly Ser Pro 500 505 510 Glu Lys Ala Arg Ser Ser Ser Ser Pro Gln His Leu Asn Val Gln Gln 515 520 525 Leu Glu Asp Met Tyr Ser Lys Met Ala Lys Thr Gln Ser Gln Pro Ile 530 535 540 Leu Asn Thr Lys Glu Met Ala Pro Gln Ser Lys Pro Pro Glu Glu Leu 545 550 555 560 Glu Met Ser Ser Met Pro Ser Pro Val Ala Pro Leu Pro Ala Arg Thr 565 570 575 Glu Gly Val Ile Asp Met Arg Ser Met Ser Ser Ile Asp Ser Phe Ile 580 585 590 Ser Cys Ala Thr Asp Phe Pro Glu Ala Thr Arg Phe Ser His Ser Pro 595 600 605 Leu Ala Ser Leu Ser Ser Lys Ala Gly Ser Ser Thr Ala Pro Glu Val 610 615 620 Gly Trp Arg Gly Ala Leu Gly Ala Ser Gly Gly Arg Leu Thr Glu Thr 625 630 635 640 Asn Pro Ile Pro Glu Thr Ser Arg Ser Gly Phe Phe Val Glu Ser Pro 645 650 655 Arg Ser Ser Met Lys Thr Asn Asn Pro Leu Lys Leu Arg Ala Leu Lys 660 665 670 Val Asn Phe Val Glu Gly Asp Pro Thr Pro Leu Leu Pro Ser Leu Gly 675 680 685 Leu Tyr His Asp Pro Leu Arg Asn Arg Gly Gly Ala Ala Ala Ala Val 690 695 700 Ala Gly Leu Glu Cys Ala Ser Leu Leu Asp Lys Pro Val Leu Ser Pro 705 710 715 720 Glu Ser Ser Ile Tyr Thr Thr Ala Ser Ala Arg Thr Pro Pro Arg Ser 725 730 735 Pro Glu Lys His Thr Ala Ile Ala Phe Asn Phe Glu Ala Gly Val His 740 745 750 His Tyr Ile Asp Thr Asp Thr Asp Asp Glu Gly Gln Leu Leu Tyr Ser 755 760 765 Val Asp Ser Ser Pro Pro Lys Ser Leu His Gly Ser Thr Ser Pro Lys 770 775 780 Phe Ser Thr Gly Ala Arg Thr Glu Lys Asn His Phe Glu Ser Ser Pro 785 790 795 800 Leu Pro Thr Ser Pro Lys Phe Leu Arg Pro Asn Cys Val Tyr Ser Ser 805 810 815 Glu Gly Leu Thr Gly Lys Gly Pro Gly Ala Gln Glu Lys Cys Lys Leu 820 825 830 Glu Asn His Thr Pro Pro Asp Val His Met Leu Pro Gly Gly Gly Ala 835 840 845 His Gly Ser Thr Arg Asp Gln Ser Ile 850 855 6 655 PRT Homo sapiens 6 Met Ala Ala Gly Val Ala Ala Trp Leu Pro Phe Ala Arg Ala Ala Ala 1 5 10 15 Ile Gly Trp Met Pro Val Ala Asn Cys Pro Met Pro Leu Ala Pro Ala 20 25 30 Asp Lys Asn Lys Arg Gln Asp Glu Leu Ile Val Leu Asn Val Ser Gly 35 40 45 Arg Arg Phe Gln Thr Trp Arg Thr Thr Leu Glu Arg Tyr Pro Asp Thr 50 55 60 Leu Leu Gly Ser Thr Glu Lys Glu Phe Phe Phe Asn Glu Asp Thr Lys 65 70 75 80 Glu Tyr Phe Phe Asp Arg Asp Pro Glu Val Phe Arg Cys Val Leu Asn 85 90 95 Phe Tyr Arg Thr Gly Lys Leu His Tyr Pro Arg Tyr Glu Cys Ile Ser 100 105 110 Ala Tyr Asp Asp Glu Leu Ala Phe Tyr Gly Ile Leu Pro Glu Ile Ile 115 120 125 Gly Asp Cys Cys Tyr Glu Glu Tyr Lys Asp Arg Lys Arg Glu Asn Ala 130 135 140 Glu Arg Leu Met Asp Asp Asn Asp Ser Glu Asn Asn Gln Glu Ser Met 145 150 155 160 Pro Ser Leu Ser Phe Arg Gln Thr Met Trp Arg Ala Phe Glu Asn Pro 165 170 175 His Thr Ser Thr Leu Ala Leu Val Phe Tyr Tyr Val Thr Gly Phe Phe 180 185 190 Ile Ala Val Ser Val Ile Thr Asn Val Val Glu Thr Val Pro Cys Gly 195 200 205 Thr Val Pro Gly Ser Lys Glu Leu Pro Cys Gly Glu Arg Tyr Ser Val 210 215 220 Ala Phe Phe Cys Leu Asp Thr Ala Cys Val Met Ile Phe Thr Gly Glu 225 230 235 240 Tyr Leu Leu Arg Leu Phe Ala Ala Pro Ser Arg Tyr Arg Phe Ile Arg 245 250 255 Ser Val Met Ser Ile Ile Asp Val Val Ala Ile Met Pro Tyr Tyr Ile 260 265 270 Gly Leu Val Met Thr Asn Asn Glu Asp Val Ser Gly Ala Phe Val Thr 275 280 285 Leu Arg Val Phe Arg Val Phe Arg Ile Phe Lys Phe Ser Arg His Ser 290 295 300 Gln Gly Leu Arg Ile Leu Gly Tyr Thr Leu Lys Ser Cys Ala Ser Glu 305 310 315 320 Leu Gly Phe Leu Leu Phe Ser Leu Thr Met Ala Ile Ile Ile Phe Ala 325 330 335 Thr Val Met Phe Tyr Ala Glu Lys Gly Ser Ser Ala Ser Lys Phe Thr 340 345 350 Ser Ile Pro Ala Ser Phe Trp Tyr Thr Ile Val Thr Met Thr Thr Leu 355 360 365 Gly Tyr Gly Asp Met Val Leu Lys Thr Ile Ala Gly Lys Ile Phe Gly 370 375 380 Ser Ile Cys Ser Leu Ser Gly Val Leu Val Ile Ala Leu Pro Val Pro 385 390 395 400 Val Ile Val Ser Asn Phe Ser Arg Ile Tyr His Gln Asn Gln Arg Ala 405 410 415 Asp Lys Arg Arg Ala Gln Lys Lys Ala Arg Leu Ala Arg Ile Arg Val 420 425 430 Ala Lys Thr Gly Ser Ser Asn Ala Tyr Leu His Ser Lys Arg Asn Gly 435 440 445 Leu Leu Asn Glu Ala Leu Glu Leu Thr Gly Thr Pro Glu Glu Glu His 450 455 460 Met Gly Lys Thr Thr Ser Leu Ile Glu Ser Gln His His His Leu Leu 465 470 475 480 His Cys Leu Glu Lys Thr Thr Gly Leu Ser Tyr Leu Val Asp Asp Pro 485 490 495 Leu Leu Ser Val Arg Thr Ser Thr Ile Lys Asn His Glu Phe Ile Asp 500 505 510 Glu Gln Met Phe Glu Gln Asn Cys Met Glu Ser Ser Met Gln Asn Tyr 515 520 525 Pro Ser Thr Arg Ser Pro Ser Leu Ser Ser His Pro Gly Leu Thr Thr 530 535 540 Thr Cys Cys Ser Arg Arg Ser Lys Lys Thr Thr His Leu Pro Asn Ser 545 550 555 560 Asn Leu Pro Ala Thr Arg Leu Arg Ser Met Gln Glu Leu Ser Thr Ile 565 570 575 His Ile Gln Gly Ser Glu Gln Pro Ser Leu Thr Thr Ser Arg Ser Ser 580 585 590 Leu Asn Leu Lys Ala Asp Asp Gly Leu Arg Pro Asn Cys Lys Thr Ser 595 600 605 Gln Ile Thr Thr Ala Ile Ile Ser Ile Pro Thr Pro Pro Ala Leu Thr 610 615 620 Pro Glu Gly Glu Ser Arg Pro Pro Pro Ala Ser Pro Gly Pro Asn Thr 625 630 635 640 Asn Ile Pro Ser Ile Thr Ser Asn Val Val Lys Val Ser Val Leu 645 650 655 7 6942 DNA Rattus norvegicus 7 tctagagccc cccacatgct cccccaccgg gtcccccgtt gcgtgaggac acctcctctg 60 aggggctccg ctcgcccctc ttcggacccc ccggggcccc ggctggccag aggatggacg 120 aggaggagga tggagcgggc gccgaggagt cgggacagcc ccgtagcttc acgcagctca 180 acgacctgtc cggggccggg ggccggcagg ggccggggtc gacggaaaag gacccgggca 240 gcgcggactc cgaggcggag gggctgccgt acccggcgct agccccggtg gttttcttct 300 acttgagcca ggacagccgc ccgcggagct ggtgtctccg cacggtctgt aacccgtggt 360 tcgagcgagt cagtatgctg gtcattcttc tcaactgtgt gactctgggt atgttcaggc 420 cgtgtgagga cattgcctgt gactcccagc gctgccggat cctgcaggcc ttcgatgact 480 tcatctttgc cttctttgct gtggaaatgg tggtgaagat ggtggccttg ggcatctttg 540 ggaagaaatg ttacctggga gacacttgga accggcttga ctttttcatt gtcattgcag 600 ggatgctgga gtattcgctg gacctgcaga acgtcagctt ctccgcagtc aggacagtcc 660 gtgtgctgcg accgctcagg gccattaacc gggtgcccag catgcgcatt ctcgtcacat 720 tactgctgga caccttgcct atgctgggca acgtcctgct gctctgtttc ttcgtctttt 780 tcatctttgg catcgtgggc gtccagctgt gggcaggact gcttcgcaac cggtgcttcc 840 tccccgagaa cttcagcctc cccctgagcg tggacctgga gccttattac cagacagaga 900 atgaggacga gagccccttc atctgctctc agcctcggga gaatggcatg agatcctgca 960 ggagtgtgcc cacactgcgt ggggaaggcg gtggtggccc accctgcagt ctggactatg 1020 agacctataa cagttccagc aacaccacct gtgtcaactg gaaccagtac tataccaact 1080 gctctgcggg cgagcacaac cccttcaaag gcgccatcaa ctttgacaac attggctatg 1140 cctggatcgc catcttccag gtcatcacac tggagggctg ggtcgacatc atgtacttcg 1200 taatggacgc tcactccttc tacaacttca tctacttcat tcttctcatc atcgtgggct 1260 ccttcttcat gatcaacctg tgcctggtgg tgattgccac gcagttctcc gagaccaaac 1320 agcgggagag tcagctgatg cgggagcagc gtgtacgatt cctgtccaat gctagcaccc 1380 tggcaagctt ctctgagcca ggcagctgct atgaggagct actcaagtac ctggtgtaca 1440 tcctccgaaa agcagcccga aggctggccc aggtctctag ggctataggc gtgcgggctg 1500 ggctgctcag cagcccagtg gcccgtagtg ggcaggagcc ccagcccagt ggcagctgca 1560 ctcgctcaca ccgtcgtctg tctgtccacc acctggtcca ccaccatcac caccaccatc 1620 accactacca cctgggtaat gggacgctca gagttccccg ggccagccca gagatccagg 1680 acagggatgc caatgggtct cgccggctca tgctaccacc accctctaca cccactccct 1740 ctgggggccc tccgaggggt gcggagtctg tacacagctt ctaccatgct gactgccact 1800 tggagccagt ccgttgccag gcaccccctc ccagatgccc atcggaggca tctggtagga 1860 ctgtgggtag tgggaaggtg taccccactg tgcataccag ccctccacca gagatactga 1920 aggataaagc actagtggag gtggccccca gccctgggcc ccccaccctc accagcttca 1980 acatcccacc tgggcccttc agctccatgc acaagctcct ggagacacag agtacgggag 2040 cctgccatag ctcctgcaaa atctccagcc cttgctccaa ggcagacagt ggagcctgcg 2100 ggccggacag ttgtccctac tgtgcccgga caggagcagg agagccagag tccgctgacc 2160 atgtcatgcc tgactcagac agcgaggctg tgtatgagtt cacacaggac gctcagcaca 2220 gtgacctccg ggatccccac agccggcggc gacagcggag cctgggccca gatgcagagc 2280 ctagttctgt gctggctttc tggaggctga tctgtgacac attccggaag atcgtagata 2340 gcaaatactt tggccgggga atcatgatcg ccatcctggt caatacactc agcatgggca 2400 tcgagtacca cgagcagccc gaggagctca ccaacgccct ggaaatcagc aacatcgtct 2460 tcaccagcct cttcgccttg gagatgctgc tgaaactgct tgtctacggt ccctttggct 2520 acattaagaa tccctacaac atctttgatg gtgtcattgt ggtcatcagt gtgtgggaga 2580 ttgtgggcca gcagggaggt ggcctgtcgg tgctgcggac cttccgcctg atgcgggtgc 2640 tgaagctggt gcgcttcctg ccggccctgc agcgccagct cgtggtgctc atgaagacca 2700 tggacaacgt ggccaccttc tgcatgctcc tcatgctgtt catcttcatc ttcagcatcc 2760 tgggcatgca tctctttggt tgcaagttcg catctgaacg ggatggggac acgttgccag 2820 accggaagaa tttcgactcc ctgctctggg ccatcgtcac tgtctttcag attctgactc 2880 aggaagactg gaataaagtc ctctacaacg gcatggcctc cacatcgtct tgggctgctc 2940 tttacttcat cgccctcatg acttttggca actatgtgct ctttaacctg ctggtggcca 3000 ttcttgtgga aggattccag gcagagggag atgccaccaa gtctgagtca gagcctgatt 3060 tcttttcgcc cagtgtggat ggtgatgggg acagaaagaa gcgcttggcc ctggtggctt 3120 tgggagaaca cgcggaacta cgaaagagcc ttttgccacc cctcatcatc catacggctg 3180 cgacaccaat gtcacacccc aagagctcca gcacaggtgt gggggaagca ctgggctctg 3240 gctctcgacg taccagtagc agtgggtccg ctgagcctgg agctgcccac catgagatga 3300 aatgtccgcc aagtgcccgc agctccccgc acagtccctg gagtgcggca agcagctgga 3360 ccagcaggcg ctccagcagg aacagcctgg gccgggcccc cagcctaaag cggaggagcc 3420 cgagcgggga gcggaggtcc ctgctgtctg gagagggcca ggagagtcag gatgaggagg 3480 aaagttcaga agaggaccgg gccagcccag caggcagtga ccatcgccac aggggttcct 3540 tggaacgtga ggccaagagt tcctttgacc tgcctgacac tctgcaggtg ccggggctgc 3600 accgcacagc cagcggccgg agctctgcct ctgagcacca agactgtaat ggcaagtcgg 3660 cttcagggcg tttggcccgc accctgagga ctgatgaccc ccaactggat ggggatgatg 3720 acaatgatga gggaaatctg agcaaagggg aacgcataca agcctgggtc agatcccggc 3780 ttcctgcctg ttgccgagag cgagattcct ggtcggccta tatctttcct cctcagtcaa 3840 ggtttcgtct cctgtgtcac cggatcatca cccacaagat gtttgaccat gtggtcctcg 3900 tcatcatctt cctcaactgt atcaccatcg ctatggagcg ccccaaaatt gacccccaca 3960 gcgctgagcg catcttcctg accctctcca actacatctt cacggcagtc tttctagctg 4020 aaatgacagt gaaggtggtg gcactgggct ggtgctttgg ggagcaggcc tacctgcgca 4080 gcagctggaa tgtgctggac ggcttgctgg tgctcatctc cgtcatcgac atcctggtct 4140 ccatggtctc cgacagcggc accaagatcc ttggcatgct gagggtgctg cggctgctgc 4200 ggaccctgcg tccactcagg gtcatcagcc gggcccaggg actgaagctg gtggtagaga 4260 ctctgatgtc atccctcaaa cccattggca acattgtggt catttgctgt gccttcttca 4320 tcatttttgg aattctcggg gtgcagctct tcaaagggaa gttcttcgtg tgtcagggtg 4380 aggacaccag gaacatcact aacaaatccg actgcgctga ggccagctac cgatgggtcc 4440 ggcacaagta caactttgac aacctgggcc aggctctgat gtccctgttt gtgctggcct 4500 ccaaggatgg ttgggttgac atcatgtatg atgggctgga tgctgtgggt gtggatcagc 4560 agcccatcat gaaccacaac ccctggatgc tgctatactt catctccttc ctcctcatcg 4620 tggccttctt tgtcctgaac atgtttgtgg gcgtggtggt ggagaacttc cataagtgca 4680 gacagcacca ggaggaggag gaggcgaggc ggcgtgagga gaagcgacta cggaggctgg 4740 agaaaaagag aaggagtaag gagaagcaga tggccgaagc ccagtgcaag ccctactact 4800 ctgactactc gagattccgg ctccttgtcc accacctgtg taccagccac tacctggacc 4860 tcttcatcac tggtgtcatc gggctgaacg tggtcactat ggccatggaa cattaccagc 4920 agccccagat cctggacgag gctctgaaga tctgcaatta catctttacc gtcatctttg 4980 tctttgagtc agttttcaaa cttgtggcct ttggcttccg ccgtttcttc caggacaggt 5040 ggaaccagct ggacctggct attgtgcttc tgtccatcat gggcatcaca ctggaggaga 5100 ttgaggtcaa tctgtcgctg cccatcaacc ccaccatcat ccgtatcatg agggtgctcc 5160 gcattgctcg agttctgaag ctgttgaaga tggctgtggg catgcgggca ctgctgcaca 5220 cggtgatgca ggccctgccc caggtgggga acctgggact tctcttcatg ttattgtttt 5280 tcatctttgc agctctgggc gtggagctct ttggagacct ggagtgtgat gagacacacc 5340 cttgtgaggg cttgggtcgg catgccacct ttaggaactt tggtatggcc tttctgaccc 5400 tcttccgagt ctccactggt gacaactgga atggtattat gaaggacacc ctccgggact 5460 gtgaccagga gtccacctgc tacaacactg tcatctcccc tatctacttt gtgtccttcg 5520 tgctgacggc ccagtttgtg ctggtcaacg tggtcatagc tgtgctgatg aagcacctgg 5580 aagaaagcaa caaagaggcc aaggaggagg ccgagctcga ggccgagctg gagctggaga 5640 tgaagacgct cagcccgcag ccccactccc cgctgggcag ccccttcctc tggcccgggg 5700 tggagggtgt caacagtact gacagcccta agcctggggc tccacacacc actgcccaca 5760 ttggagcagc ctcgggcttc tcccttgagc accccacgat ggtaccccac cccgaggagg 5820 tgccagtccc cctaggacca gacctgctga ctgtgaggaa gtctggtgtc agccggacgc 5880 actctctgcc caatgacagc tacatgtgcc gcaatgggag cactgctgag agatccctag 5940 gacacagggg ctgggggctc cccaaagccc agtcaggctc catcttgtcc gttcactccc 6000 aaccagcaga caccagctgc atcctacagc ttcccaaaga tgtgcactat ctgctccagc 6060 ctcatggggc tcccacctgg ggcgccatcc ctaaactacc cccacctggc cgctcccctc 6120 tggctcagag gcctctcagg cgccaggcag caataaggac tgactccctg gatgtgcagg 6180 gcctgggtag ccgggaagac ctgttgtcag aggtgagtgg gccctcctgc cctctgaccc 6240 ggtcctcatc cttctggggc gggtcgagca tccaggtgca gcagcgttcc ggcatccaga 6300 gcaaagtctc caagcacatc cgcctgccag ccccttgccc aggcctggaa cccagctggg 6360 ccaaggaccc tccagagacc agaagcagct tagagctgga cacggagctg agctggattt 6420 caggagacct ccttcccagc agccaggaag aacccctgtt cccacgggac ctgaagaagt 6480 gctacagtgt agagacccag agctgcaggc gcaggcctgg gttctggcta gatgaacagc 6540 ggagacactc cattgctgtc agctgtctgg acagcggctc ccaaccccgc ctatgtccaa 6600 gcccctcaag cctcgggggc caacctcttg ggggtcctgg gagccggcct aagaaaaaac 6660 tcagcccacc cagtatctct atagaccccc cggagagcca gggctctcgg cccccatgca 6720 gtcctggtgt ctgcctcagg aggagggcgc cggccagtga ctctaaggat ccctcggtct 6780 ccagccccct tgacagcacg gctgcctcac cctccccaaa gaaagacacg ctgagtctct 6840 ctggtttgtc ttctgaccca acagacatgg acccctgagt cctacccact ctcccccatc 6900 acctttctcc accgggtgca gatcctacgt ccgcctcctg gg 6942 8 6990 DNA Homo sapiens 8 atggctgaga gcgcctcccc gccctcctca tctgcagcag ccccagccgc tgagccagga 60 gtcaccacgg agcagcccgg accccggagc cccccatcct ccccgccagg cctggaggag 120 cctctggatg gagctgatcc tcatgtccca cacccagacc tggcgcctat tgccttcttc 180 tgcctgcgac agaccaccag cccccggaac tggtgcatca agatggtgtg caacccgtgg 240 tttgaatgtg tcagcatgct ggtgatcctg ctgaactgcg tgacacttgg catgtaccag 300 ccgtgcgacg acatggactg cctgtccgac cgctgcaaga tcctgcaggt ctttgatgac 360 ttcatcttta tcttctttgc catggagatg gtgctcaaga tggtggccct ggggattttt 420 ggcaagaagt gctacctcgg ggacacatgg aaccgcctgg atttcttcat cgtcatggca 480 gggatggtcg agtactccct ggaccttcag aacatcaacc tgtcagccat ccgcaccgtg 540 cgcgtcctga ggcccctcaa agccatcaac cgcgtgccca gtatgcggat cctggtgaac 600 ctgctcctgg acacactgcc catgctgggg aatgtcctgc tgctctgctt ctttgtcttc 660 ttcatctttg gcatcatagg tgtgcagctc tgggcgggcc tgctgcgtaa ccgctgcttc 720 ctggaggaga acttcaccat acaaggggat gtggccttgc ccccatacta ccagccggag 780 gaggatgatg agatgccctt catctgctcc ctgtcgggcg acaatgggat aatgggctgc 840 catgagatcc ccccgctcaa ggagcagggc cgtgagtgct gcctgtccaa ggacgacgtc 900 tacgactttg gggcggggcg ccaggacctc aatgccagcg gcctctgtgt caactggaac 960 cgttactaca atgtgtgccg cacgggcagc gccaaccccc acaagggtgc catcaacttt 1020 gacaacatcg gttatgcttg gattgtcatc ttccaggtga tcactctgga aggctgggtg 1080 gagatcatgt actacgtgat ggatgctcac tccttctaca acttcatcta cttcatcctg 1140 cttatcatag tgggctcctt cttcatgatc aacctgtgcc tcgttgtcat agcgacccag 1200 ttctcggaga ccaagcaacg ggagcaccgg ctgatgctgg agcagcggca gcgctacctg 1260 tcctccagca cggtggccag ctacgccgag cctggcgact gctacgagga gatcttccag 1320 tatgtctgcc acatcctgcg caaggccaag cgccgcgccc tgggcctcta ccaggccctg 1380 cagagccggc gccaggccct gggcccggag gccccggccc ccgccaaacc tgggccccac 1440 gccaaggagc cccggcacta ccatgggaag actaagggtc agggagatga agggagacat 1500 ctcggaagcc ggcattgcca gactttgcat gggcctgcct cccctggaaa tgatcactcg 1560 ggaagagagc tgtgcccgca acatagcccc ctggatgcga cgccccacac cctggtgcag 1620 cccatccccg ccacgctggc ttccgatccc gccagctgcc cttgctgcca gcatgaggac 1680 ggccggcggc cctcgggcct gggcagcacc gactcgggcc aggagggctc gggctccggg 1740 agctccgctg gtggcgagga cgaggcggat ggggacgggg cccggagcag cgaggacgga 1800 gcctcctcag aactggggaa ggaggaggag gaggaggagc aggcggatgg ggcggtctgg 1860 ctgtgcgggg atgtgtggcg ggagacgcga gccaagctgc gcggcatcgt ggacagcaag 1920 tacttcaacc ggggcatcat gatggccatc ctggtcaaca ccgtcagcat gggcatcgag 1980 caccacgagc agccggagga gctgaccaac atcctggaga tctgcaatgt ggtcttcacc 2040 agcatgtttg ccctggagat gatcctgaag ctggctgcat ttgggctctt cgactacctg 2100 cgtaacccct acaacatctt cgacagcatc attgtcatca tcagcatctg ggagatcgtg 2160 gggcaggcgg acggtgggct gtcggtgctg cggaccttcc ggctgctgcg cgtgctgaaa 2220 ctggtgcgct tcatgcctgc cctgcggcgc cagctcgtgg tgctcatgaa gaccatggac 2280 aacgtggcca ccttctgcat gctgctcatg ctcttcatct tcatcttcag catccttggg 2340 atgcatattt ttggctgcaa gttcagcctc cgcacggaca ctggagacac ggtgcccgac 2400 aggaagaact tcgactccct gctgtgggcc atcgtcactg tgttccagat cctcacccag 2460 gaggactgga acgtcgttct ctacaatggc atggcctcca cttctccctg ggcctccctc 2520 tactttgtcg ccctcatgac cttcggcaac tatgtgctct tcaacctgct ggtggccatc 2580 ctggtggagg gcttccaggc ggagggtgac gccaatcgct cctactcgga cgaggaccag 2640 agctcatcca acatagaaga gtttgataag ctccaggaag gcctggacag cagcggagat 2700 cccaagctct gcccaatccc catgaccccc aatgggcacc tggaccccag tctcccactg 2760 ggtgggcacc taggtcctgc tggggctgcg ggacctgccc cccgactctc actgcagccg 2820 gaccccatgc tggtggccct gggctcccga aagagcagtg tcatgtctct agggaggatg 2880 agctatgacc agcgctccct gtccagctcc cggagctcct actacgggcc atggggccgc 2940 agcgcggcct gggccagccg tcgctccagc tggaacagcc tcaagcacaa gccgccgtcg 3000 gcggagcatg agtccctgct ctctgcggag cgcggcggcg gcgcccgggt ctgcgaggtt 3060 gccgcggacg aggggccgcc gcgggccgca cccctgcaca ccccacacgc ccaccacatt 3120 catcacgggc cccatctggc gcaccgccac cgccaccacc gccggacgct gtccctcgac 3180 aacagggact cggtggacct ggccgagctg gtgcccgcgg tgggcgccca cccccgggcc 3240 gcctggaggg cggcaggccc ggcccccggg catgaggact gcaatggcag gatgcccagc 3300 atcgccaaag acgtcttcac caagatgggc gaccgcgggg atcgcgggga ggatgaggag 3360 gaaatcgact acaccctgtg cttccgcgtc cgcaagatga tcgacgtcta taagcccgac 3420 tggtgcgagg tccgcgaaga ctggtctgtc tacctcttct ctcccgagaa caggttccgg 3480 gtcctgtgtc agaccattat tgcccacaaa ctcttcgact acgtcgtcct ggccttcatc 3540 tttctcaact gcatcaccat cgccctggag cggcctcaga tcgaggccgg cagcaccgaa 3600 cgcatctttc tcaccgtgtc caactacatc ttcacggcca tcttcgtggg cgagatgaca 3660 ttgaaggtag tctcgctggg cctgtacttc ggcgagcagg cgtacctacg cagcagctgg 3720 aacgtgctgg atggctttct tgtcttcgtg tccatcatcg acatcgtggt gtccctggcc 3780 tcagccgggg gagccaagat cttgggggtc ctccgagtct tgcggctcct gcgcacccta 3840 cgccccctgc gtgtcatcag ccgggcgccg ggcctgaagc tggtggtgga gacactcatc 3900 tcctccctca agcccatcgg caacatcgtg ctcatctgct gtgccttctt catcatcttt 3960 ggcatcctgg gagtgcagct cttcaagggc aagttctacc actgtctggg cgtggacacc 4020 cgcaacatca ccaaccgctc ggactgcatg gccgccaact accgctgggt ccatcacaaa 4080 tacaacttcg acaacctggg ccaggctctg atgtccctct ttgtcctggc atccaaggat 4140 ggttgggtga acatcatgta caatggactg gatgctgttg ctgtggacca gcagcctgtg 4200 accaaccaca acccctggat gctgctgtac ttcatctcct tcctgctcat cgtcagcttc 4260 tttgtgctca acatgtttgt gggtgtcgtg gtggagaact tccacaagtg ccggcagcac 4320 caggaggctg aagaggcacg gcggcgtgag gagaagcggc tgcggcgcct ggagaagaag 4380 cgccggaagg cccagcggct gccctactat gccacctatt gtcacacccg gctgctcatc 4440 cactccatgt gcaccagcca ctacctggac atcttcatca ccttcatcat ctgcctcaac 4500 gtggtcacca tgtccctgga gcactacaat cagcccacgt ccctggagac agccctcaag 4560 tactgcaact atatgttcac cactgtcttt gtgctggagg ctgtgctgaa gctggtggca 4620 tttggtctga ggcgcttctt caaggaccga tggaaccagc tggacctggc cattgtgcta 4680 ctgtcagtca tgggcatcac cctggaggag atcgagatca atgcggccct gcccatcaat 4740 cccaccatca tccgcatcat gagggttctg cgcattgccc gagtgctgaa gctgttgaag 4800 atggccacag gaatgcgggc cctgctggac acggtggtgc aagctttgcc ccaggtgggc 4860 aacctgggcc tcctcttcat gctgctcttc ttcatctatg ctgctctcgg ggtggagctc 4920 tttgggaagc tggtctgcaa cgacgagaac ccgtgcgagg gcatgagccg gcatgccacc 4980 ttcgagaact tcggcatggc cttcctcaca ctcttccagg tctccacggg tgacaactgg 5040 aacgggatca tgaaggacac gctgcgggac tgcacccacg acgagcgcag ctgcctgagc 5100 agcctgcagt ttgtgtcgcc gctgtacttc gtgagcttcg tgctcaccgc gcagttcgtg 5160 ctcatcaacg tggtggtggc tgtgctcatg aagcacctgg acgacagcaa caaggaggcg 5220 caggaggacg ccgagatgga tgccgagctc gagctggaga tggcccatgg cctgggccct 5280 ggcccgaggc tgcctaccgg ctccccgggc gcccctggcc gagggccggg aggggcgggc 5340 ggcgggggcg acaccgaggg cggcttgtgc cggcgctgct actcgcctgc ccaggagaac 5400 ctgtggctgg acagcgtctc tttaatcatc aaggactcct tggaggggga gctgaccatc 5460 atcgacaacc tgtcgggctc catcttccac cactactcct cgcctgccgg ctgcaagaag 5520 tgtcaccacg acaagcaaga ggtgcagctg gctgagacgg aggccttctc cctgaactca 5580 gacaggtcct cgtccatcct gctgggtgac gacctgagtc tcgaggaccc cacagcctgc 5640 ccacctggcc gcaaagacag caagggtgag ctggacccac ctgagcccat gcgtgtggga 5700 gacctgggcg aatgcttctt ccccttgtcc tctacggccg tctcgccgga tccagagaac 5760 ttcctgtgtg agatggagga gatcccattc aaccctgtcc ggtcctggct gaaacatgac 5820 agcagtcaag cacccccaag tcccttctcc ccggatgcct ccagccctct cctgcccatg 5880 ccagccgagt tcttccaccc tgcagtgtct gccagccaga aaggcccaga aaagggcact 5940 ggcactggaa ccctccccaa gattgcgctg cagggctcct gggcatctct gcggtcacca 6000 agggtcaact gtaccctcct ccggcaggcc accgggagcg acacgtcgct ggacgccagc 6060 cccagcagct ccgcgggcag cctgcagacc acgctcgagg acagcctgac cctgagcgac 6120 agcccccggc gtgccctggg gccgcccgcg cctgctccag gaccccgggc cggcctgtcc 6180 cccgccgctc gccgccgcct gagcctgcgc ggccggggcc tcttcagcct gcgggggctg 6240 cgggcgcatc agcgcagcca cagcagcggg ggctccacca gcccgggctg cacccaccac 6300 gactccatgg acccctcgga cgaggagggc cgcggtggcg cgggcggcgg gggcgcgggc 6360 agcgagcact cggagaccct cagcagcctc tcgctcacct ccctcttctg cccgccgccc 6420 ccgccgccag cccccggcct cacgcccgcc aggaagttca gcagcaccag cagcctggcc 6480 gcccccggcc gcccccacgc cgccgccctg gcccacggcc tggcccggag cccctcgtgg 6540 gccgcggacc gcagcaagga cccccccggc cgggcaccgc tgcccatggg cctgggcccc 6600 ttggcgcccc cgccgcaacc gctccccgga gagctggagc cgggagacgc cgccagcaag 6660 aggaagagat gagggtcgca ggggcccccg gccgcccacc gcccgccccg tctcaccttc 6720 tttacctcag gagccaggag cagacagcaa tacttcgtcc acacctggga tcgcgcaggg 6780 cccgcagggc acaggcgccc gacagccggg ctgagcggag tctgggttag ccaggcctgc 6840 gtggcccatg gtggcccttc cagtgcatat acatacatat atatatatat atgcatatat 6900 atatatatat atatatatat gtgtatacac acacacatag acagacatat atatatatat 6960 ttattttttt tactgagagc ttatgacttc 6990 9 9014 DNA Mus musculus 9 gtgtgttgca catgtctgtg tgagtacagg cacacatgtg catgcaagtg gttgcagaag 60 gcagaagatc actttggatc ccttggggct ggagttatag gtgcttgtga gccaccagac 120 atggtacttg taattgagaa gcaagtggtc ccaaccacag tgccatctct ccagctccca 180 ctttctttct ttttgaccac aactctcccc tttataaaag aggaagaaag ttattcccaa 240 gccggggaaa cactcacaac aggctccttc ttttaactta gtggagaagt cggggcagcc 300 tcaaaaacag tgagtaggtc acaactctag tactctacta agcacttgag caaattacaa 360 gatagcaatt ggtatgcagg agccaaagta tgatgagggt tggatgagca tgtgctaagc 420 acagccatcc tcttttgtct taattggagc agatatactg caagcctctc tctgtctaga 480 gataacgttt attttatttg gatgcatgag tattttgctt acatgtatgt atgggtacta 540 tgtgtgtgcc tggagcctgc agtggtcacg agaggggatc agatcccatg gaacggagct 600 cggcgcggcg cggcccggag cggcggcggc agtggcggcg gcggcgacgc ttcccgcggg 660 ctcgccctca ggtgttcgcg gctgccgtcg ccgaagatcg cgggtcgggg cctcgcggcg 720 atcgccctgg gcgggccgga gacgcctcgg gccccctggc ggctcggggt ccacccggcg 780 ccgcgggccc gccgctttcc ctcgcctcgc ctttgcgcct cttctcgctc tgcctctcca 840 tttattattc ttatcatttt tattttcaaa tggtgtagcc gccagaggtg cggtgctaaa 900 ttcttggaag gggcccggat gtactgagga tgcattacaa tctcacgaaa ggaggcggta 960 gtggaaagca gcagtttttg gtgtttggtg caataatggg gatcaggtaa tcacccgaag 1020 ggagcaagaa ccactgcgga tccacggctt cctggatttg cgcgagagcc gccggcctcg 1080 gaggagggat ccatcccgag ccgctcgcgg ctgttgctgc atttcttcct ctttgtggct 1140 tctcctttcc aagcagtttt tggccaatgg tcaatgaaaa cacgaggatg tacgttccag 1200 aggaaaacca ccaaggttcc aactatggga gcccacgccc agctcatgcc aacatgaatg 1260 ccaatgcagc tgcaggactt gctcccgagc acatccctac tccaggggca gcactgtcct 1320 ggcaggcagc catcgatgcc gcccggcagg ccaagctcat gggcagtgct ggcaacgcaa 1380 ccatctctac cgtcagttcc acacagcgga agcggcagca gtatgggaaa cccaagaagc 1440 aggggggcac aaccgccaca cggccgcccc gggctctgct gtgtctgacc ctgaagaacc 1500 ctatccggag ggcgtgcata agcattgttg aatggaaacc atttgaaatc attattttac 1560 tgactatttt tgccaattgt gtggccttag caatctatat tccctttccg gaagacgact 1620 ccaacgccac caactccaac ctggaacgag tggagtatct cttcctcatc atttttaccg 1680 tggaagcatt tttaaaagta attgcctacg gacttctctt ccaccccaac gcttacctcc 1740 gcaatggttg gaatttactg gattttataa tcgtggttgt agggcttttt agtgcaattt 1800 tagaacaagc aaccaaagct gatggggcca atgctctagg agggaaagga gctggattcg 1860 acgtgaaggc actgagagcg ttccgcgtgc tccgtccact gcggctagtg tccggagtcc 1920 caagtctcca ggtggtcctg aactccatca tcaaggccat ggtgcctctg ctgcacattg 1980 cccttcttgt gctcttcgtc atcatcattt atgctattat cggcctggag ctcttcatgg 2040 gaaagatgca caagacctgc tacaaccagg agggcataat agatgttccg gcagaagagg 2100 atccttcccc ttgtgctttg gagacaggcc atgggcgaca gtgtcagaac gggaccgtgt 2160 gcaaacccgg gtgggatggg cccaagcacg gcatcaccaa cttcgacaac ttcgccttcg 2220 ccatgctgac ggtgttccag tgtatcacca tggagggctg gacagacgtg ctgtactgga 2280 tgcaagacgc tatgggctat gagttgccct gggtgtattt tgtcagtctg gtcatctttg 2340 gatccttttt cgttctaaat ctggttctcg gtgttttgag cggggagttt tccaaagaga 2400 gggagaaagc caaagcccga ggagatttcc agaagcttcg agagaagcag caactagaag 2460 aagatctcaa aggctacctg gactggatca cccaggcaga agacattgac cccgagaatg 2520 aggacgaggg catggatgaa gacaagcctc gaaacatgag catgcccaca agtgagactg 2580 agtctgtcaa cactgaaaac gtggctggag gtgacatcga gggagaaaac tgtggagcca 2640 ggcttgccca tcggatctcc aaatccaaat tcagccgcta ctggcgcagg tggaatcgat 2700 tctgcagaag aaaatgccgt gcagcagtta agtccaacgt cttctactgg ctcgtgatct 2760 tcctggtgtt cctcaacacc ctcaccattg cctccgaaca ttacaaccag cctcactggc 2820 tcacagaagt gcaagacaca gccaataaag ccctcctggc ccttttcact gcagaaatgc 2880 tcctgaagat gtacagcctg ggtcttcagg cctattttgt gtccctcttc aaccgctttg 2940 actgtttcat tgtgtgtggg ggcatcctgg agaccatcct ggtggagacg aagatcatgt 3000 ctcccctggg catctctgtg ctgagatgtg tgcggttgct caggatcttc aagatcacca 3060 ggtactggaa ttccttgagc aaccttgtgg catccttgct gaactcagtg cgctccattg 3120 cctccctgct gctgctcctc ttcctcttca tcatcatctt ctccctcctg gggatgcagc 3180 tctttggagg gaagttcaat ttcgatgaga tgcagacccg taggagcacg ttcgataact 3240 tcccgcagtc tctcctcact gtgtttcaga tcctgaccgg ggaggactgg aattcggtga 3300 tgtatgatgg gatcatggct tatggcggcc cctcttttcc agggatgtta gtctgtattt 3360 acttcatcat cctcttcatc tgtggaaatt atatcctact gaatgtgttc ttggccattg 3420 cggtggacaa cctggctgat gcggagagcc tgacctcagc ccaaaaggag gaggaagaag 3480 agaaggagag gaagaagctg gccaggactg ccagcccaga aaagaaacag gaggtgatgg 3540 agaagccagc cgtggaggag agcaaagagg agaaaattga actgaaatcc attacagccg 3600 atggagaatc cccacccact accaagatca acatggatga cctccagccc agtgaaaacg 3660 aggataagag tccccactcc aacccagaca ctgcagggga agaggatgaa gaggagccag 3720 agatgcctgt ggggccacgc ccccggcccc tgtctgagct gcaccttaag gaaaaggcag 3780 ttcccatgcc ggaagccagt gcatttttca tcttcagccc aaacaacagg ttccgcctgc 3840 agtgccaccg tattgtcaat gacacgatct tcaccaacct catcctcttc ttcattctgc 3900 tcagcagcat ctctctggct gctgaggacc ccgtccagca cacctccttc aggaaccata 3960 tcctaggcaa tgcagactat gtcttcacta gtatctttac attagaaatt atccttaaga 4020 tgactgctta cggggctttc ctgcacaagg gctctttctg ccgaaactac ttcaatatcc 4080 tggacctgct ggtggttagc gtgtccctca tctcctttgg catccagtcc agcgcgatca 4140 acgttgtgaa gattttacga gtgctgcgag tcctcagacc cctgagggcc atcaacaggg 4200 ccaaggggct aaagcatgtg gttcagtgcg tgtttgtggc catccggacc atcgggaaca 4260 tcgtaattgt caccactctg ctgcagttca tgttcgcctg cattggggtc cagctcttca 4320 agggaaagct ctatacctgt tcggatagtt ctaaacagac ggaggcagaa tgcaagggta 4380 actatatcac atacaaagat ggagaggtcg atcaccccat tatccagcct cgaagctggg 4440 agaacagcaa gtttgacttt gacaatgttt tggcagccat gatggctctc ttcaccgtct 4500 ccaccttcga agggtggcca gagctgctgt accgctccat tgactcccac acagaagaca 4560 agggccccat ctacaactac cgtgtggaga tctccatctt cttcatcatc tatatcatca 4620 tcattgcctt cttcatgatg aacatcttcg tgggtttcgt cattgtcacc ttccaggagc 4680 agggggaaca agagtacaag aactgtgagc tggacaagaa ccagagacaa tgtgtggaat 4740 atgccctcaa ggcccgaccc ttgcgaaggt acatccccaa gaaccagcac cagtacaaag 4800 tgtggtacgt ggtcaactct acctacttcg agtatctgat gttcgttctc atcctgctca 4860 acaccatctg cctggccatg cagcactatg gccagagctg cctcttcaaa atcgccatga 4920 atatactcaa catgcttttc accggcctct tcacagtgga gatgatcctg aagctcattg 4980 ccttcaaacc caagggttac tttagtgatc cctggaatgt ttttgacttc ctcatcgtca 5040 ttgggagcat aattgatgtc attctcagtg agactaatcc agctgaacat acccaatgct 5100 ctccctctat gagtgcagag gagaactccc gcatctccat caccttcttc cgcctcttcc 5160 gggtcatgcg cctggtgaag ctgctgagcc gcggggaagg catccgaacc ctgctgtgga 5220 ccttcatcaa gtccttccag gctctgccct atgtggctct tttgattgtg atgctgttct 5280 ttatctatgc agtgattggg atgcaggtgt ttgggaagat tgccctgaat gacaccacag 5340 agatcaatcg gaacaacaac ttccagacgt tcccccaggc tgtgttactg ctgttcaggt 5400 gtgccaccgg agaggcctgg caggacatca tgctggcctg catgccaggc aagaagtgtg 5460 ccccagagtc tgagcccagc aacagcacgg aaggggagac cccctgtggc agcagctttg 5520 ctgtcttcta cttcatcagc ttctacatgc tctgtgcctt cctgatcatc aacctctttg 5580 tagctgttat catggacaac tttgactacc tgactaggga ttggtctatc ctcggtcccc 5640 atcacctgga tgaattcaag agaatctggg ccgagtatga ccctgaagcc aagggtcgga 5700 tcaaacactt ggatgtggtg accctcctcc gtcgaattca gcccccactg ggttttggga 5760 aattgtgtcc tcaccgtgtg gcctgcaaac gcctggtgtc catgaacatg cctctgaaca 5820 gcgatggcac agtcatgttc aatgctaccc tgtttgccct cgtcaggaca gccctgagga 5880 tcaaaacaga agggaaccta gagcaagcca atgaggagct tcgggccatc atcaagaaaa 5940 tctggaagag gactagcatg aagctgttgg accaggtggt gccccctgca ggcgatgacg 6000 aggtcacagt gggcaagttc tatgccacct tcctgatcca agagtacttc aggaaattca 6060 agaagcgaaa agagcagggg ctggtgggca agccctcaca aaggaatgca ctgtccctcc 6120 aggctggctt gcgcaccttg catgacattg ggcctgagat ccggcgggcc atctctgggg 6180 atctgactgc tgaggaggag ttggacaagg ctatgaagga ggcggtgtct gctgcctccg 6240 aagatgacat cttcaggagg gctggaggcc tgttcggcaa ccatgtcacc tactatcaga 6300 gtgacagcag gggcaacttt cctcagacgt tcgccaccca gcgcccactg cacatcaaca 6360 agacagggaa caaccaagct gacactgagt caccgtccca tgagaagctg gtggactcca 6420 cgttcacccc cagcagctac tcatccacgg gctccaatgc caacatcaac aatgccaaca 6480 acactgccct gggccgcttc ccccatcccg ctggctactc cagcacggtc agcactgtgg 6540 agggccatgg gcctcccttg tcccctgctg tccgagtaca ggaggcagca tggaagctca 6600 gctctaagag gtgccactcc cgagagagcc agggagccac ggtgaatcag gagatatttc 6660 cagatgagac ccgcagcgta aggatgagtg aagaagccga gtactgcagt gagcccagcc 6720 tgctctccac agatatgttc tcctaccagg aagatgaaca ccgacaactg acctgcccag 6780 aggaggacaa gagggagatc cagccatctc caaagaggag tttccttcgc tctgcctctc 6840 taggtcgaag ggcctccttc catctggaat gtctaaagcg acaaaaggat caagggggag 6900 acatctctca gaagacagcc ttgcccttgc atctggttca tcatcaggca ttggcagtgg 6960 caggcttgag ccccctcctg cagagaagcc attctcctac cacattcccc aggccgtgcc 7020 ccacaccccc tgtcactcca ggcagccggg gcagacccct acggcccatc cctaccctac 7080 ggctggaggg ggcagagtcc agcgagaaac tcaacagcag cttcccatcc atccactgca 7140 gctcctggtc tgaggagacg acagcctgta gtgggagcag cagcatggcc cggagagccc 7200 ggcccgtctc cctcaccgtg cccagccagg ctggagctcc agggagacag ttccatggca 7260 gtgccagcag cctggtggaa gcggtcttga tttcagaagg actgggacag tttgctcaag 7320 atcccaagtt catcgaggtc accacccagg agctggctga cgcctgcgac atgacaatag 7380 aggagatgga gaacgccgca gacaacatcc tcagtggggg cgcccagcag agccccaacg 7440 gcaccctctt accttttgtg aactgcaggg acccggggca ggacagggct gtggccccag 7500 aggacgagag ctgcgcatat gccctggggc gaggccggag cgaggaggcg ctcgcggaca 7560 gcaggtccta cgtcagcaac ctgtagtcct cagggctggc gagacgcggg tggttttttt 7620 attcgtttca atgttcctaa tgggttcgtt tcagaagtgc ctcactgttc tcgtgacctg 7680 gaggtaaccg gaacagcgtc ttcattcact gctgtcggga taagcctcag agctgggcgg 7740 tgtacggagt cggcttttca ggggagaagg ccaaggccgt ggtgcggggg ctccagcacc 7800 ttccgcggca gcaccgccca aaggacccca cccccacccc tgagcaaaag ggtgttttcc 7860 ccttgcttgt ataaacagtc atttgcacat gttctgtctg agcctggccg tctctatgga 7920 gcagggcccc agggatctat ggcaggaatg ggccagcgcc cccagtagga gccgggaggt 7980 ggctgcgagg ttcccagcag tgcaggtctg gtccctatgg tcccttcagg gactctttcc 8040 ctgcaaggag ctgagatgca ggtggcagga gccagtgcag atcacaccac ccgccctcag 8100 ctagccaggc caggggggcg caggctgctg cctggtgctc ggggtttcat ggtttgaggg 8160 ttcttgtcag catgttgcga ctttctgggg tttggtttct ttattactat ttgttgtgtt 8220 ttcccacggg gaggggagga ataagagcgg ttacaactgc gcggcctcac ttcactgttt 8280 ccacatttgc atttgcgtat ttaagtcgga tttggtttga ttgtattctt taaatggtgc 8340 ggtccacccc caccgccacc cccacccccc actggagcaa gggttcaata tcaccagaga 8400 aaggttttac ctgctctgtg tctgcccagt aacttgttcc aatttcctta agtaaaagca 8460 acttttttct ttctttcgag tttggttgag catcacaatc agcaggctaa caggcagtta 8520 gatcaggcgg tgtgcgcctg ggcgattgag ctgggctcct ttctgtgctg ggcatatgga 8580 ctggttcaag agagaagaaa tatgggcatc tttgtgtcac acttgtgtcc atagtatgtg 8640 cgtatgtgca cccacgtggt atgtgtgcgc cccaccccac ccctgcacaa aagcctgtag 8700 aaccccgttt gggtttgact gcagggagtt ctaaatctgg ggctatttga aagcaagaac 8760 aaaccactgt ctctgcttct gcttctgaaa cgagaatcgg taactgcatt tttctgtccc 8820 acgagatatg caaaagcaat gcaataatat ccattttaaa atatggttgt gagttgtgtc 8880 agcattaaaa ttctatttta aaaaaaaaac cacgaaattt aagggaaaaa ctcaagaaga 8940 cattttgctt cgatatattc tgtgtaatgt tttattgcat tgataatgtt tctgttgaag 9000 aaactgttat actt 9014 10 7648 DNA Homo sapiens 10 atggacgagg aggaggatgg agcgggcgcc gaggagtcgg gacagccccg gagcttcatg 60 cggctcaacg acctgtcggg ggccgggggc cggccggggc cggggtcagc agaaaaggac 120 ccgggcagcg cggactccga ggcggagggg ctgccgtacc cggcgctggc cccggtggtt 180 ttcttctact tgagccagga cagccgcccg cggagctggt gtctccgcac ggtctgtaac 240 ccctggtttg agcgcatcag catgttggtc atccttctca actgcgtgac cctgggcatg 300 ttccggccat gcgaggacat cgcctgtgac tcccagcgct gccggatcct gcaggccttt 360 gatgacttca tctttgcctt ctttgccgtg gagatggtgg tgaagatggt ggccttgggc 420 atctttggga aaaagtgtta cctgggagac acttggaacc ggcttgactt tttcatcgtc 480 atcgcaggga tgctggagta ctcgctggac ctgcagaacg tcagcttctc agctgtcagg 540 acagtccgtg tgctgcgacc gctcagggcc attaaccggg tgcccagcat gcgcatcctt 600 gtcacgttgc tgctggatac gctgcccatg ctgggcaacg tcctgctgct ctgcttcttc 660 gtcttcttca tcttcggcat cgtcggcgtc cagctgtggg cagggctgct tcggaaccga 720 tgcttcctac ctgagaattt cagcctcccc ctgagcgtgg acctggagcg ctattaccag 780 acagagaacg aggatgagag ccccttcatc tgctcccagc cacgcgagaa cggcatgcgg 840 tcctgcagaa gcgtgcccac gctgcgcggg gacgggggcg gtggcccacc ttgcggtctg 900 gactatgagg cctacaacag ctccagcaac accacctgtg tcaactggaa ccagtactac 960 accaactgct cagcggggga gcacaacccc ttcaagggcg ccatcaactt tgacaacatt 1020 ggctatgcct ggatcgccat cttccaggtc atcacgctgg agggctgggt cgacatcatg 1080 tactttgtga tggatgctca ttccttctac aatttcatct acttcatcct cctcatcatc 1140 gtgggctcct tcttcatgat caacctgtgc ctggtggtga ttgccacgca gttctcagag 1200 accaagcagc gggaaagcca gctgatgcgg gagcagcgtg tgcggttcct gtccaacgcc 1260 agcaccctgg ctagcttctc tgagcccggc agctgctatg aggagctgct caagtacctg 1320 gtgtacatcc ttcgtaaggc agcccgcagg ctggctcagg tctctcgggc agcaggtgtg 1380 cgggttgggc tgctcagcag cccagcaccc ctcgggggcc aggagaccca gcccagcagc 1440 agctgctctc gctcccaccg ccgcctatcc gtccaccacc tggtgcacca ccaccaccac 1500 catcaccacc actaccacct gggcaatggg acgctcaggg ccccccgggc cagcccggag 1560 atccaggaca gggatgccaa tgggtcccgc aggctcatgc tgccaccacc ctcgacgcct 1620 gccctctccg gggccccccc tggtggcgca gagtctgtgc acagcttcta ccatgccgac 1680 tgccacttag agccagtccg ctgccaggcg ccccctccca ggtccccatc tgaggcatcc 1740 ggcaggactg tgggcagcgg gaaggtgtat cccaccgtgc acaccagccc tccaccggag 1800 acgctgaagg agaaggcact agtagaggtg gctgccagct ctgggccccc aaccctcacc 1860 agcctcaaca tcccacccgg gccctacagc tccatgcaca agctgctgga gacacagagt 1920 acaggtgcct gccaaagctc ttgcaagatc tccagccctt gcttgaaagc agacagtgga 1980 gcctgtggtc cagacagctg cccctactgt gcccgggccg gggcagggga ggtggagctc 2040 gccgaccgtg aaatgcctga ctcagacagc gaggcagttt atgagttcac acaggatgcc 2100 cagcacagcg acctccggga cccccacagc cggcggcaac ggagcctggg cccagatgca 2160 gagcccagct ctgtgctggc cttctggagg ctaatctgtg acaccttccg aaagattgtg 2220 gacagcaagt actttggccg gggaatcatg atcgccatcc tggtcaacac actcagcatg 2280 ggcatcgaat accacgagca gcccgaggag cttaccaacg ccctagaaat cagcaacatc 2340 gtcttcacca gcctctttgc cctggagatg ctgctgaagc tgcttgtgta tggtcccttt 2400 ggctacatca agaatcccta caacatcttc gatggtgtca ttgtggtcat cagcgtgtgg 2460 gagatcgtgg gccagcaggg gggcggcctg tcggtgctgc ggaccttccg cctgatgcgt 2520 gtgctgaagc tggtgcgctt cctgccggcg ctgcagcggc agctggtggt gctcatgaag 2580 accatggaca acgtggccac cttctgcatg ctgcttatgc tcttcatctt catcttcagc 2640 atcctgggca tgcatctctt cggctgcaag tttgcctctg agcgggatgg ggacaccctg 2700 ccagaccgga agaattttga ctccttgctc tgggccatcg tcactgtctt tcagatcctg 2760 acccaggagg actggaacaa agtcctctac aatggtatgg cctccacgtc gtcctgggcg 2820 gccctttatt tcattgccct catgaccttc ggcaactacg tgctcttcaa tttgctggtc 2880 gccattctgg tggagggctt ccaggcggag gaaatcagca aacgggaaga tgcgagtgga 2940 cagttaagct gtattcagct gcctgtcgac tcccaggggg gagatgccaa caagtccgaa 3000 tcagagcccg atttcttctc acccagcctg gatggtgatg gggacaggaa gaagtgcttg 3060 gccttggtgt ccctgggaga gcacccggag ctgcggaaga gcctgctgcc gcctctcatc 3120 atccacacgg ccgccacacc catgtcgctg cccaagagca ccagcacggg cctgggcgag 3180 gcgctgggcc ctgcgtcgcg ccgcaccagc agcagcgggt cggcagagcc tggggcggcc 3240 cacgagatga agtcaccgcc cagcgcccgc agctctccgc acagcccctg gagcgctgca 3300 agcagctgga ccagcaggcg ctccagccgg aacagcctcg gccgtgcacc cagcctgaag 3360 cggagaagcc caagtggaga gcggcggtcc ctgttgtcgg gagaaggcca ggagagccag 3420 gatgaagagg agagctcaga agaggagcgg gccagccctg cgggcagtga ccatcgccac 3480 agggggtccc tggagcggga ggccaagagt tcctttgacc tgccagacac actgcaggtg 3540 ccagggctgc atcgcactgc cagtggccga gggtctgctt ctgagcacca ggactgcaat 3600 ggcaagtcgg cttcagggcg cctggcccgg gccctgcggc ctgatgaccc cccactggat 3660 ggggatgacg ccgatgacga gggcaacctg agcaaagggg aacgggtccg cgcgtggatc 3720 cgagcccgac tccctgcctg ctgcctcgag cgagactcct ggtcagccta catcttccct 3780 cctcagtcca ggttccgcct cctgtgtcac cggatcatca cccacaagat gttcgaccac 3840 gtggtccttg tcatcatctt ccttaactgc atcaccatcg ccatggagcg ccccaaaatt 3900 gacccccaca gcgctgaacg catcttcctg accctctcca attacatctt caccgcagtc 3960 tttctggctg aaatgacagt gaaggtggtg gcactgggct ggtgcttcgg ggagcaggcg 4020 tacctgcgga gcagttggaa cgtgctggac gggctgttgg tgctcatctc cgtcatcgac 4080 attctggtgt ccatggtctc tgacagcggc accaagatcc tgggcatgct gagggtgctg 4140 cggctgctgc ggaccctgcg cccgctcagg gtgatcagcc gggcgcaggg gctgaagctg 4200 gtggtggaga cgctgatgtc ctcactgaaa cccatcggca acattgtagt catctgctgt 4260 gccttcttca tcattttcgg catcttgggg gtgcagctct tcaaagggaa gtttttcgtg 4320 tgccagggcg aggataccag gaacatcacc aataaatcgg actgtgccga ggccagttac 4380 cggtgggtcc ggcacaagta caactttgac aaccttggcc aggccctgat gtccctgttc 4440 gttttggcct ccaaggatgg ttgggtggac atcatgtacg atgggctgga tgctgtgggc 4500 gtggaccagc agcccatcat gaaccacaac ccctggatgc tgctgtactt catctcgttc 4560 ctgctcattg tggccttctt tgtcctgaac atgtttgtgg gtgtggtggt ggagaacttc 4620 cacaagtgtc ggcagcacca ggaggaagag gaggcccggc ggcgggagga gaagcgccta 4680 cgaagactgg agaaaaagag aaggaatcta atgctggacg atgtaattgc ttccggcagc 4740 tcagccagcg ctgcgtcaga agcccagtgc aaaccttact actccgacta ctcccgcttc 4800 cggctcctcg tccaccactt gtgcaccagc cactacctgg acctcttcat cacaggtgtc 4860 atcgggctga acgtggtcac catggccatg gagcactacc agcagcccca gattctggat 4920 gaggctctga agatctgcaa ctacatcttc actgtcatct ttgtcttgga gtcagttttc 4980 aaacttgtgg cctttggttt ccgtcggttc ttccaggaca ggtggaacca gctggacctg 5040 gccattgtgc tgctgtccat catgggcatc acgctggagg aaatcgaggt caacgcctcg 5100 ctgcccatca accccaccat catccgcatc atgagggtgc tgcgcattgc ccgagtgctg 5160 aagctgctga agatggctgt gggcatgcgg gcgctgctgg acacggtgat gcaggccctg 5220 ccccaggtgg ggaacctggg acttctcttc atgttgttgt ttttcatctt tgcagctctg 5280 ggcgtggagc tctttggaga cctggagtgt gacgagacac acccctgtga gggcctgggc 5340 cgtcatgcca cctttcggaa ctttggcatg gccttcctaa ccctcttccg agtctccaca 5400 ggtgacaatt ggaatggcat tatgaaggac accctccggg actgtgacca ggagtccacc 5460 tgctacaaca cggtcatctc gcctatctac tttgtgtcct tcgtgctgac ggcccagttc 5520 gtgctagtca acgtggtgat cgccgtgctg atgaagcacc tggaggagag caacaaggag 5580 gccaaggagg aggccgagct agaggctgag ctggagctgg agatgaagac cctcagcccc 5640 cagccccact cgccactggg cagccccttc ctctggcctg gggtcgaggg ccccgacagc 5700 cccgacagcc ccaagcctgg ggctctgcac ccagcggccc acgcgagatc agcctcccac 5760 ttttccctgg agcaccccac ggacaggcag ctgtttgaca ccatatccct gctgatccag 5820 ggctccctgg agtgggagct gaagctgatg gacgagctgg caggcccagg gggccagccc 5880 tctgccttcc cttctgcccc cagcctggga ggctccgacc cacagatccc tctagctgag 5940 atggaggctc tgtctctgac gtcagagatt gtgtctgaac cgtcctgctc tctagctctg 6000 acggatgact ctttgcctga tgacatgcac acactcttac ttagtgccct ggagagcaat 6060 atgcagcccc accccacgga gctgccagga ccagacttac tgactgtgcg gaagtctggg 6120 gtcagccgaa cgcactctct gcccaatgac agctacatgt gtcggcatgg gagcactgcc 6180 gaggggcccc tgggacacag gggctggggg ctccccaaag ctcagtcagg ctccgtcttg 6240 tccgttcact cccagccagc agataccagc tacatcctgc agcttcccaa agatgcacct 6300 catctgctcc agccccacag cgccccaacc tggggcacca tccccaaact gcccccacca 6360 ggacgctccc ctttggctca gaggccactc aggcgccagg cagcaataag gactgactcc 6420 ttggacgttc agggtctggg cagccgggaa gacctgctgg cagaggtgag tgggccctcc 6480 ccgcccctgg cccgggccta ctctttctgg ggccagtcaa gtacccaggc acagcagcac 6540 tcccgcagcc acagcaagat ctccaagcac atgaccccgc cagccccttg cccaggccca 6600 gaacccaact ggggcaaggg ccctccagag accagaagca gcttagagtt ggacacggag 6660 ctgagctgga tttcaggaga cctcctgccc cctggcggcc aggaggagcc cccatcccca 6720 cgggacctga agaagtgcta cagcgtggag gcccagagct gccagcgccg gcctacgtcc 6780 tggctggatg agcagaggag acactctatc gccgtcagct gcctggacag cggctcccaa 6840 ccccacctgg gcacagaccc ctctaacctt gggggccagc ctcttggggg gcctgggagc 6900 cggcccaaga aaaaactcag cccgcctagt atcaccatag acccccccga gagccaaggt 6960 cctcggaccc cgcccagccc tggtatctgc ctccggagga gggctccgtc cagcgactcc 7020 aaggatccct tggcctctgg cccccctgac agcatggctg cctcgccctc cccaaagaaa 7080 gatgtgctga gtctctccgg tttatcctct gacccagcag acctggaccc ctgagtcctg 7140 ccccactttc ccactcacct ttctccactg ggtgccaagt cctagctcct cctcctgggc 7200 tatattcctg acaaaagttc catatagaca ccaaggaggc ggaggcgctc ctccctgcct 7260 cagtggctct gggtacctgc aagcagaact tccaaagaga gttaaaagca gcagccccgg 7320 caactctggc tccaggcaga aggagaggcc cggtgcagct gaggttcccg acaccagaag 7380 ctgttgggag aaagcaatac gtttgtgcag aatctctatg tatattctat tttattaaat 7440 taattgaatc tagtatatgc gggatgtacg acattttgtg actgaagaga cttgtttcct 7500 tctactttta tgtgtctcag aatatttttg aggcgaaggc gtctgtctct tggctatttt 7560 aacctaaaat aacagtctag ttatattccc tcttcttgca aagcacaagc tgggaccgcg 7620 agcacattgc agccccaacg gtggccca 7648 11 6073 DNA Caenorhabditis elegans 11 accactttga cccggtcacc tgaaaatgct acgtcagcca gttccggaac tgcgcagttt 60 tcagtccctc tctaaatatg caggcggacc gagatcagtt ctcggtagga gaacatcagc 120 aatcacagtc aatcgaagac aatcacaatc gacacgacga catgaggatg ttgaggcact 180 gggctcgatc gaaggctcga aagaaactct gcagctgtcg gaacacggac gattggcctc 240 ctcctcggag gcctcccctt ctcggtggga gggccgacag atcgagtggg ggaatgaaga 300 gcaaattgaa gaggaaagtg aacttccgta tccggggttt gctgagccag cacttcgatg 360 tttttatcaa gccagacctc caaggaaatg ggcgcttcaa atggtgatga gtccttggtt 420 tgaccgaata acaatggctg tgattatgat taattgtgta accctcggga tgtacaggcc 480 ttgtgaagat ggtccagact gtgacactta ccggtgtcaa atccttgata taattgacaa 540 ttgcatattt gtctattttg catttgaaat ggtgataaaa ataatggctc tagggtttta 600 cggtcctgcg gcttatatgt ctgatacatg gaatcgtctg gactttttca ttgttatggc 660 aggaatcgct gagtttgtat tacacgagta tctcggagga aacatcaatt taacagcaat 720 cagaacggtt cgagtactga ggccgcttcg agcggtcaat cgaataccat cgatgaggat 780 tttagtcaat ttgttactcg acacattacc catgcttgga aatgtgcttc ttttatgttt 840 tttcgttttc ttcatttttg gaattgttgg tgttcaatta tgggcgggtt tattacgaaa 900 tcgatgtgtc attaatttac caaaaacaat atcggagaat caatctgcgt tgttcaacaa 960 tgtaaaactg acaaggtttt acattccgga agacacatcg ctagaatata tttgcagtca 1020 accagacgca aacgggttac acacttgctc aaatcttcca ccatacactg tcgacggagt 1080 gaagtgtaac cttacactag atgaatacga caaagtaacg aacgactctt gtatcaactg 1140 gaatatttat tacaacgaat gtcaggtgat gcaacgaaat ccatttcaag gatcagtttc 1200 tttcgacaat atcggttttg cgtgggtcgc tatttttctc gtcatatcac ttgaagggtg 1260 gacggatata atgtactatg tacaggacgc tcattctttt tggaattgga tctattttgt 1320 tcttctcatt gtgatcggtg cttttttcat gatcaatcta tgccttgttg ttattgctac 1380 tcagtttgct gaaacaaagc ggcgggagac tgaacgaatg ctacaagaac gaaaaatgct 1440 actaaataga gattctatat cgtgtactgg aagtgagatt ggtggcgctt cttccaaaga 1500 agaaggagat actgtttatg cagcttttgt tagatttatc ggacacacct ttcggagaac 1560 aaaacgagca gcgaaaaaaa agtacactgc ctacatggaa gaaagagcag agcgaaaaag 1620 ttccgaacga caacaacgga ggaagtcaaa acttgatgat atggccacac tttcaaggat 1680 cgaggaaaaa gctgaagacg aagaagatga aaccaccata actcgtgaaa acggagatga 1740 tcaaatcgag caaaatggtg atggagtccg gataaagcgc gtaaaaattg aagaagaacc 1800 caagatcaaa ataggaaacg gtaattcgaa tggaccgcat tacaaacact ccagcagcga 1860 tgaagaatct gatgaggatg gcgaagagga ccaagtttac gatggggaag aagccaagaa 1920 gaagagtaca ccttccaagc tctggtggtt tcgagaaaaa attcagaaat tcgttatttg 1980 tgatcacttc actagaggga ttcttgttgc aattttggtg aatacgttga gcatgggtgt 2040 ggagtaccat caacaaccgg aaatattaac tgtcattctg gaatattcga atttattttt 2100 cactgctttg tttgctttgg aaatgcttct taagatcatt gcaagtggat tgtttggtta 2160 tttagctgat ggattcaacc ttttcgacgg aggaattgtc gcattgagtg ttcttgagtt 2220 atttcaagaa ggtaaaggag gtctatcagt tcttcgtact tttcgccttc ttcgaattct 2280 gaaattggtt cgcttcatgc ctgctcttcg atatcaactg gttgtgatgc tccgaacaat 2340 ggacaatgtc actgtgtttt ttggactttt ggttcttttc atctttatct tcagcattct 2400 cggaatgaat ctgtttgggt gcaaattttg caaagtcgaa gagaaatttc ttggaggcct 2460 tgcgaaaaag tgtgaaagaa aaaactttga cacgttgctc tgggcgctga tcactgtgtt 2520 tcagattctt acacaagaag attggaacat ggttttattc aacggtatgg ctcaaacaaa 2580 cccatgggca gctctttact ttgtggcgct catgacattt ggtaattacg ttcttttcaa 2640 cttacttgta gctatcttgg tagaaggatt ccaagaaagc aaggaagaag aaaagcgaca 2700 attggaagag gatgcgagaa agcaagctgt agaagaagaa gacgaaagaa agcgagaatt 2760 ggagcttata attgccaaaa caacgtcacc tgctttcaat aatggagtag cacctgcaga 2820 atgtacttgt caaagaccat cctccccgga agaatcacca tctccgagat tgctgtctgc 2880 aaattaccac ccatctcctg aaaggaaaca ctctgcaaat ttggatgcca tcattgataa 2940 aagattagtt ctaagaaatt cggcaccttt cgatagatca ccagtatctg aaggacgtga 3000 tgattctaga ctcaatcgtc acgccagtct tgtacttcct gtcgctaatg gagttccgta 3060 tcggcgacaa agagttcaca gttggagtgg gctttgtcat catttcaatc cgaactgccc 3120 tgtacatgga agaagagcac tcattgaaac ttatgcacga gaaaaatttc tagaagctag 3180 tcaagagcta aaacaggctc tcgctgagga agaaaaaaga aatgaagcca agcaaaacac 3240 gtttgtgaga aaacttttga aaaaaacgtg ccttcacaac cgaactgaat tttcactatt 3300 tcttatgggc ccaaaaaacc cgctacgcat aaaatgccta caaacaactc aaaagaaatg 3360 gttcgattac accgtattgt ttttcattgg aatcaactgt ataacactgg ctatggaacg 3420 accatcaatt cctcctgata gttttgaaag gcaatttctt catatttctg ggtacatttt 3480 cacagtgatt tttactggtg aaatgatgat gaaggttatt gcaaatggtt gtttcattgg 3540 gcaagcagcg tattttaaag atggttggaa cattctcgat ggaattcttg ttgtcatttc 3600 cttaatcaac attgcgtttg aacttctggc aactggcgat tctccaaaaa tatttggtgt 3660 tataagagtg ttaaggctac ttcgtgcatt gaggccttta cgagttatca atagggctcc 3720 gggagttaag cttgtagtaa tgacattaat atccagtctg aaacctatcg gaaacattgt 3780 tctgatttgc tgcacattct tcattatctt tggcatcctc ggtgttcagt tgttcaaagg 3840 tatgatgtac cattgcattg gacctgaagt tggaaacgtt acaacaaaag cggattgcat 3900 tgaagattac cgaaacaaat gggttaatca tcgttacaac tttgacaacc tcggtcaggc 3960 tcttatgtca cttttcgttc tttcaagtaa agatggatgg gtctcgatca tgtatcaagg 4020 aatcgacgct gtaggggttg acgtgcaacc aattgagaat tacaatgaat ggagaatgat 4080 ttactttatt tcattcttat tgcttgttgg attctttgtg ctgaacatgt tcgtaggagt 4140 tgtggttgag aactttcata agtgcaaaga agcattggaa aaagaaatga gagaaaaaga 4200 gaaagaaaag aggctgaaga gaaagctgaa acggcagaag tttgaggaga gtatggctgg 4260 aaaacggaaa aaaatggaaa ggaattatcc ttattaccat gattatggtc atacaaggct 4320 tttcttgcac ggaattgtca cctccaaata cttcgaccta gcgatcgccg cagtaattgg 4380 tatcaatgtc atatctatgg ctatggagtt ctatatgatg ccaatgggac tgaaatacgt 4440 tctcaaagct ctcaattact ttttcacagc agtcttcaca ctagaagctg ctatgaagct 4500 gattgctttg ggttttaaac gtttctttat tgaaaaatgg aatcgcttgg atatgttcat 4560 tgttattttg tctattgcgg gcataatttt cgaagagttt gaagctctcg aacttccaat 4620 taatccaaca atcattcgtg tcatgcgagt gctccggata gccagagttc tgaaactgct 4680 gaaaatggcc aaaggaattc gatcattgtt ggacacagtg ggagaagcgt tgccccaggt 4740 tggaaatctc gggtctctgt tcttccttct tttcttcata tttgctgcac ttggtgttga 4800 actgtttgga aaactggagt gctctgaaga tcatccgtgt gatggattag gagaacatgc 4860 gcattttaaa aattttggaa tggctttttt aacactcttt cgaatagcga cgggtgataa 4920 ttggaatgga attatgaagg atgccctccg tgatgactgt gattcctccg atcactgtga 4980 aacaaactgc tgcgttgatc caatcctggc accatgcttc ttcgtaattt tcgtcttgat 5040 ctcacaattt gtacttgtca atgtagtagt cgctgtactt atgaaacatc tggaagaaag 5100 taacaagcga gatgcggaag gaccggcaga accaacaggt gaaaacatcg agaacgagat 5160 cacaaagtcc gacgatgacg aaattgtgga agaacacgaa ccactcgcaa ttgaacatgt 5220 taaagagggt gaacttgatg aagaagaaga gacagaagaa ggtcccacca ctcaaatacc 5280 agacgggcat ggtggtatta aacggttatc catgcaggtt ctggaacaag aattaatcga 5340 agtcgagaga catttggaag aaagatatcg gagggcaagc gagtgtctcg gcggagaact 5400 tcagcctttg aatcccggag agatcgaaga tctagacgat cccgagttca gaccacggag 5460 tagatcacat agaccacgag caagaacaaa cagtgcgttg agcaataaaa gccgtggatc 5520 acacaagtct gctttatagc ctattcactt atcaagaaga aaatatcatc aacttttttt 5580 gcaatttttc atagttgtat atccacccca ctttttatgg aaccatctca tatttagaat 5640 tctttgcttt gccaaaacct ttggttgatc aatatcagat tgttcgttta ttactggtaa 5700 catttgtcat aactcaaaaa atccctcttt tttcaatttc cctctgaacc ttttttatcg 5760 catgtatgaa acttgtatga aagaatttga aacaaataaa acgaaaccta tgcttttttc 5820 aattgtcaac ttatatttcc ggtccatgtt tcctctactt ttcgcttctg catttcattt 5880 gccttcctgt tagaaattaa atctacttga aaaagaactg catcttccaa agtgttcact 5940 tcaaactgat cttttctgat gtttaatatt gttcgaaatt ctaatatcaa ctattttctt 6000 ggtttattgc ttttttgtct ttttgtcttt ttgtcttctt cctttcattc attattgaaa 6060 aaatgaataa ttg 6073 12 5905 DNA Rattus norvegicus 12 tctggagcca tacggtgccc tgatcctctg taccaggaag acagggtgaa gatggaggag 60 aggtactacc cggtgatctt cccggacgag cggaatttcc gccccttcac ttccgactct 120 ctggctgcca tagagaagcg gattgctatc caaaaggaga ggaagaagtc caaagacaag 180 gcggcagctg agccccagcc tcggcctcag cttgacctaa aggcctccag gaagttacct 240 aagctttatg gtgacattcc ccctgagctt gtagcgaagc ctctggaaga cctggaccca 300 ttctacaaag accataagac attcatggtg ttgaacaaga agagaacaat ttatcgcttc 360 agcgccaagc gggccttgtt cattctgggg ccttttaatc ccctcagaag cttaatgatt 420 cgtatctctg tccattcagt ctttagcatg ttcatcatct gcacggtgat catcaactgt 480 atgttcatgg cgaattctat ggagagaagt ttcgacaacg acattcccga atacgtcttc 540 attgggattt atattttaga agctgtgatt aaaatattgg caagaggctt cattgtggat 600 gagttttcct tcctccgaga tccgtggaac tggctggact tcattgtcat tggaacagcg 660 atcgcaactt gttttccggg cagccaagtc aatctttcag ctcttcgtac cttccgagtg 720 ttcagagctc tgaaggcgat ttcagttatc tcaggtctga aggtcatcgt aggtgccctg 780 ctgcgctcgg tgaagaagct ggtagacgtg atggtcctca ctctcttctg cctcagcatc 840 tttgccctgg tcggtcagca gctgttcatg ggaattctga accagaagtg tattaagcac 900 aactgtggcc ccaaccctgc atccaacaag gattgctttg aaaaggaaaa agatagcgaa 960 gacttcataa tgtgtggtac ctggctcggc agcagaccct gtcccaatgg ttctacgtgc 1020 gataaaacca cattgaaccc agacaataat tatacaaagt ttgacaactt tggctggtcc 1080 tttctcgcca tgttccgggt tatgactcaa gactcctggg agaggcttta ccgacagatc 1140 ctgcggacct ctgggatcta ctttgtcttc ttcttcgtgg tggtcatctt cctgggctcc 1200 ttctacctgc ttaacctaac cctggctgtt gtcaccatgg cttatgaaga acagaacaga 1260 aatgtagctg ctgagacaga ggccaaggag aaaatgtttc aggaagccca gcagctgtta 1320 agggaggaga aggaggctct ggttgccatg ggaattgaca gaagttccct taattccctt 1380 caagcttcat ccttttcccc gaagaagagg aagtttttcg gtagtaagac aagaaagtcc 1440 ttctttatga gagggtccaa gacggcccaa gcctcagcgt ctgattcaga ggacgatgcc 1500 tctaaaaatc cacagctcct tgagcagacc aaacgactgt cccagaactt gccagtggat 1560 ctctttgatg agcacgtgga ccccctccac aggcagagag cgctgagcgc tgtcagtatc 1620 ttaaccatca ccatgcagga acaagaaaaa ttccaggagc cttgtttccc atgtgggaaa 1680 aatttggcct ctaagtacct ggtgtgggac tgtagccctc agtggctgtg cataaagaag 1740 gtcctgcgga ccatcatgac ggatcccttt actgagctgg ccatcaccat ctgcatcatc 1800 atcaataccg ttttcttagc cgtggagcac cacaacatgg atgacaactt aaagaccata 1860 ctgaaaatag gaaactgggt tttcacggga attttcatag cggaaatgtg tctcaagatc 1920 atcgcgctcg acccttacca ctacttccgg cacggctgga atgtttttga cagcatcgtg 1980 gccctcctga gtctcgctga tgtgctctac aacacactgt ctgataacaa taggtctttc 2040 ttggcttccc tcagagtgct gagggtcttc aagttagcca aatcctggcc cacgttaaac 2100 actctcatta agatcatcgg ccactccgtg ggcgcgcttg gaaacctgac tgtggtcctg 2160 actatcgtgg tcttcatctt ttctgtggtg ggcatgcggc tcttcggcac caagtttaac 2220 aagaccgcct acgccaccca ggagcggccc aggcggcgct ggcacatgga taatttctac 2280 cactccttcc tggtggtgtt ccgcatcctc tgtggggaat ggatcgagaa catgtggggc 2340 tgcatgcagg atatggacgg ctccccgttg tgcatcattg tctttgtcct gataatggtg 2400 atcgggaagc ttgtggtgct taacctcttc attgccttgc tgctcaattc cttcagcaat 2460 gaggagaagg atgggagcct ggaaggagag accaggaaaa ccaaagtgca gctagccctg 2520 gatcggttcc gccgggcctt ctccttcatg ctgcacgctc ttcagagttt ttgttgcaag 2580 aaatgcagga ggaaaaactc gccaaagcca aaagagacaa cagaaagctt tgctggtgag 2640 aataaagact caatcctccc ggatgcgagg ccctggaagg agtatgatac agacatggct 2700 ttgtacactg gacaggccgg ggctccgctg gccccactcg cagaggtaga ggacgatgtg 2760 gaatattgtg gtgaaggcgg tgccctaccc acctcacaac atagtgctgg agttcaggcc 2820 ggtgacctcc ctccagagac caagcagctc actagcccgg atgaccaagg ggttgaaatg 2880 gaagtatttt ctgaagaaga tctgcattta agcatacaga gtcctcgaaa gaagtctgac 2940 gcagtgagca tgctctcgga atgcagcaca attgacctga atgatatctt tagaaattta 3000 cagaaaacag tttcccccaa aaagcagcca gatagatgct ttcccaaggg ccttagttgt 3060 cactttctat gccacaaaac agacaagaga aagtccccct gggtcctgtg gtggaacatt 3120 cggaaaacct gctaccaaat cgtgaagcac agctggtttg agagtttcat aatctttgtt 3180 attctgctga gcagtggagc gctgatattt gaagatgtca atctccccag ccggccccaa 3240 gttgagaaat tactaaggtg taccgataat attttcacat ttattttcct cctggaaatg 3300 atcctgaagt gggtggcctt tggattccgg aggtatttca ccagtgcctg gtgctggctt 3360 gatttcctca ttgtggtggt gtctgtgctc agtctcatga atctaccaag cttgaagtcc 3420 ttccggactc tgcgggccct gagacctctg cgggcgctgt cccagtttga aggaatgaag 3480 gttgtcgtct acgccctgat cagcgccata cctgccattc tcaatgtctt gctggtctgc 3540 ctcattttct ggctcgtatt ttgtatcttg ggagtaaatt tattttctgg gaagtttgga 3600 aggtgcatta acgggacaga cataaatatg tatttggatt ttaccgaagt tccgaaccga 3660 agccaatgta acattagtaa ttactcgtgg aaggtcccgc aggtcaactt tgacaacgtg 3720 gggaatgcct atctcgccct gctgcaagtg gcaacctata agggctggct ggaaatcatg 3780 aatgctgctg tcgattccag agagaaagac gagcagccgg actttgaggc gaacctctac 3840 gcgtatctct actttgtggt ttttatcatc ttcggctcct tctttaccct gaacctcttt 3900 atcggtgtta ttattgacaa cttcaatcag cagcagaaaa agttaggtgg ccaagacatt 3960 tttatgacag aagaacagaa gaaatattac aatgcaatga aaaagttagg aaccaagaaa 4020 cctcaaaagc ccatcccaag gcccctgaac aaatgtcaag cctttgtgtt cgacctggtc 4080 acaagccagg tctttgacgt catcattctg ggtcttattg tcttaaatat gattatcatg 4140 atggctgaat ctgccgacca gcccaaagat gtgaagaaaa cctttgatat cctcaacata 4200 gccttcgtgg tcatctttac catagagtgt ctcatcaaag tctttgcttt gaggcaacac 4260 tacttcacca atggctggaa cttatttgat tgtgtggtcg tggttctttc tatcattagt 4320 accctggttt cccgcttgga ggacagtgac atttctttcc cgcccacgct cttcagagtc 4380 gtccgcttgg ctcggattgg tcgaatcctc aggctggtcc gggctgcccg gggaatcagg 4440 accctcctct ttgctttgat gatgtctctc ccctctctct tcaacatcgg tctgctgctc 4500 ttcctggtga tgttcattta cgccatcttt gggatgagct ggttttccaa agtgaagaag 4560 ggctccggga tcgacgacat cttcaacttc gagaccttta cgggcagcat gctgtgcctc 4620 ttccagataa ccacttcggc tggctgggat accctcctca accccatgct ggaggcaaaa 4680 gaacactgca actcctcctc ccaagacagc tgtcagcagc cgcagatagc cgtcgtctac 4740 ttcgtcagtt acatcatcat ctccttcctc atcgtggtca acatgtacat cgctgtgatc 4800 ctcgagaact tcaacacagc cacggaggag agcgaggacc ctctgggaga ggacgacttt 4860 gaaatcttct atgaggtctg ggagaagttt gaccccgagg cgtcgcagtt catccagtat 4920 tcggccctct ctgactttgc ggacgccctg ccggagccgt tgcgtgtggc caagccgaat 4980 aagtttcagt ttctagtgat ggacttgccc atggtgatgg gcgaccgcct ccattgcatg 5040 gatgttctct ttgctttcac taccagggtc ctcggggact ccagcggctt ggataccatg 5100 aaaaccatga tggaggagaa gtttatggag gccaaccctt ttaagaagct ctacgagccc 5160 atagtcacca ccaccaagag gaaggaggag gagcaaggcg ccgccgtcat ccagagggcc 5220 taccggaaac acatggagaa gatggtcaaa ctgaggctga aggacaggtc aagttcatcg 5280 caccaggtgt tttgcaatgg agacttgtcc agcttggatg tggccaaggt caaggttcac 5340 aatgactgaa ccctcatctc cacccctacc tcactgcctc acagcttagc ctccagcctc 5400 tggcgagcag gcggcagact cactgaacac aggccgttcg atctgtgttt ttggctgaac 5460 gaggtgacag gttggcgtcc atttttaaat gactcttgga aagatttcat gtagagagat 5520 gttagaaggg actgcaaagg acaccgacca taacggaagg cctggaggac agtccaactt 5580 acataaagat gagaaacaag aaggaaagat cccaggaaaa cttcagattg tgttctcagt 5640 acattcccca atgtgtctgt tcggtgtttt gagtatgtga cctgccacat gtagctcttt 5700 tttgcatgta cgtcaaaacc ctgcagtaag ttaatagctt gctacgggtg ttcctaccag 5760 catcacagaa ttgggtgtat gactcaaacc taaaagcatg actctgactt gtcagtcagc 5820 accccgactt tcagacgctc caatctctgt cccaggtgtc taacgaataa ataggtaaaa 5880 gaaaaaaaaa aaaaaaaaaa aaaaa 5905 13 8131 DNA Homo sapiens misc_feature (6499)..(6752) n is any nucleotide a, c, g, t (u) 13 aatgtgcagg atgacaagat ggagcaaaca gtgcttgtac caccaggacc tgacagcttc 60 aacttcttca ccagagaatc tcttgcggct attgaaagac gcattgcaga agaaaaggca 120 aagaatccca aaccagacaa aaaagatgac gacgaaaatg gcccaaagcc aaatagtgac 180 ttggaagctg gaaagaacct tccatttatt tatggagaca ttcctccaga gatggtgtca 240 gagcccctgg aggacctgga cccctactat atcaataaga aaacttttat agtattgaat 300 aaagggaagg ccatcttccg gttcagtgcc acctctgccc tgtacatttt aactcccttc 360 aatcctctta ggaaaatagc tattaagatt ttggtacatt cattattcag catgctaatt 420 atgtgcacta ttttgacaaa ctgtgtgttt atgacaatga gtaaccctcc tgattggaca 480 aagaatgtag aatacacctt cacaggaata tatacttttg aatcacttat aaaaattatt 540 gcaaggggat tctgtttaga agattttact ttccttcggg atccatggaa ctggctcgat 600 ttcactgtca ttacatttgc gtacgtcaca gagtttgtgg acctgggcaa tgtctcggca 660 ttgagaacat tcagagttct ccgagcattg aagacgattt cagtcattcc aggcctgaaa 720 accattgtgg gagccctgat ccagtctgtg aagaagctct cagatgtaat gatcctgact 780 gtgttctgtc tgagcgtatt tgctctaatt gggctgcagc tgttcatggg caacctgagg 840 aataaatgta tacaatggcc tcccaccaat gcttccttgg aggaacatag tatagaaaag 900 aatataactg tgaattataa tggtacactt ataaatgaaa ctgtctttga gtttgactgg 960 aagtcatata ttcaagattc aagatatcat tatttcctgg agggtttttt agatgcacta 1020 ctatgtggaa atagctctga tgcaggccaa tgtccagagg gatatatgtg tgtgaaagct 1080 ggtagaaatc ccaattatgg ctacacaagc tttgatacct tcagttgggc ttttctgtcc 1140 ttgtttcgac taatgactca ggacttctgg gaaaatcttt atcaactgac attacgtgct 1200 gctgggaaaa cgtacatgat attttttgtg ttggtcattt tcttgggctc attctaccta 1260 ataaatttga tcctggctgt ggtggccatg gcctacgagg aacagaatca ggccaccttg 1320 gaagaagcag aacagaaaga ggccgaattt cagcagatga ttgaacagct taaaaagcaa 1380 caggaggcag ctcagcaggc agcaacggca actgcctcag aacattccag agagcccagt 1440 gcagcaggca ggctctcaga cagctcatct gaagcctcta agttgagttc caagagtgct 1500 aaggaaagaa gaaatcggag gaagaaaaga aaacagaaag agcagtctgg tggggaagag 1560 aaagatgagg atgaattcca aaaatctgaa tctgaggaca gcatcaggag gaaaggtttt 1620 cgcttctcca ttgaagggaa ccgattgaca tatgaaaaga ggtactcctc cccacaccag 1680 tctttgttga gcatccgtgg ctccctattt tcaccaaggc gaaatagcag aacaagcctt 1740 ttcagcttta gagggcgtgc aaaggatgtg ggatctgaga acgacttcgc agatgatgag 1800 cacagcacct ttgaggataa cgagagccgt agagattcct tgtttgtgcc ccgacgacac 1860 ggagagagac gcaacagcaa cctgagtcag accagtaggt catcccggat gctggcagtg 1920 tttccagcga atgggaagat gcacagcact gtggattgca atggtgtggt ttccttggtt 1980 ggtggacctt cagttcctac atcgcctgtt ggacagcttc tgccaggggg aacaaccact 2040 gaaactgaaa tgagaaagag aaggtcaagt tctttccacg tttccatgga ctttctagaa 2100 gatccttccc aaaggcaacg agcaatgagt atagccagca ttctaacaaa tacagtagaa 2160 gaacttgaag aatccaggca gaaatgccca ccctgttggt ataaattttc caacatattc 2220 tcaatctggg actgttctcc atattggtta aaagtgaaac atgttgtcaa cctggtcgtg 2280 atggacccat ttgttgacct ggccatcacc atctgtattg tcttaaatac tcttttcatg 2340 gccatggagc actatccaat gacggaccat ttcaataatg tgcttacagt aggaaacttg 2400 gttttcactg ggatctttac agcagaaatg tttctgaaaa ttattgccat ggatccttac 2460 tattatttcc aagaaggctg gaatatcttt gacggtttta ttgtgacgct tagcctggta 2520 gaacttggac tcgccaatgt ggaaggatta tctgttctcc gttcatttcg attgctgcga 2580 gttttcaagt tggcaaaatc ttggccaacg ttaaatatgc taataaagat catcggcaat 2640 tccgtggggg ctctgggaaa tttaaccctc gtcttggcca tcatcgtctt catttttgcc 2700 gtggtcggca tgcagctctt tggtaaaagc tacaaagatt gtgtctgcaa gatcgccagt 2760 gattgtcaac tcccacaacg ctggcacatg aatgacttct tccactcctt cctgattgtg 2820 ttccgcgtgc tgtgtgggga gtggatagag accatgtggg actgtatgga ggttgctggt 2880 caagccatgt gccttactgt cttcatgatg gtcatggtga ttggaaacct agtggtcctg 2940 aatctctttc tggccttgct tctgagctca tttagtgcag acaaccttgc agccactgat 3000 gatgataatg aaatgaataa tctccaaatt gctgtggata ggatgcacaa aggagtagct 3060 tatgtgaaaa gaaaaatata tgaatttatt caacagtcct tcattaggaa acaaaagatt 3120 ttagatgaaa ttaaaccact tgatgatcta aacaacaaga aagacagttg tatgtccaat 3180 catacaacag aaattgggaa agatcttgac tatcttaaag atgtaaatgg aactacaagt 3240 ggtataggaa ctggcagcag tgttgaaaaa tacattattg atgaaagtga ttacatgtca 3300 ttcataaaca accccagtct tactgtgact gtaccaattg ctgtaggaga atctgacttt 3360 gaaaatttaa acacggaaga ctttagtagt gaatcggatc tggaagaaag caaagagaaa 3420 ctgaatgaaa gcagtagctc atcagaaggt agcactgtgg gacatcggcg ccctgtagaa 3480 gaacagcccg tagtggaacc tgaagaaact cttgaaccag aagcttgttt cactgaaggc 3540 tgtgtacaaa gattcaagtg ttgtcaaatc aatgtggaag aaggcagagg aaaacaatgg 3600 tggaacctga gaaggacgtg tttccgaata gttgaacata actggtttga gaccttcatt 3660 gttttcatga ttctccttag tagtggtgct ctggcatttg aagatatata tattgatcag 3720 cgaaagacga ttaagacgat gttggaatat gctgacaagg ttttcactta cattttcatt 3780 ctggaaatgc ttctaaaatg ggtggcatat ggctatcaaa catatttcac caatgcctgg 3840 tgttggctgg acttcttaat tgttgatgtt tcattggtca gtttaacagc aaatgccttg 3900 ggttactcag aacttggagc catcaaatct ctcaggacac taagagctct gagacctcta 3960 agagccttat ctcgatttga agggatgagg gtggttgtga atgccctttt aggagcaatt 4020 ccatccatca tgaatgtgct tctggtttgt cttatattct ggctaatttt cagcatcatg 4080 ggcgtaaatt tgtttgctgg caaattctac cactgtatta acaccacaac tggtgacagg 4140 tttgacatcg aagacgtgaa taatcatact gattgcctaa aactaataga aagaaatgag 4200 actgctcgat ggaaaaatgt gaaagtaaac tttgataatg taggatttgg gtatctctct 4260 ttgcttcaag ttgccacatt caaaggatgg atggatataa tgtatgcagc agttgattcc 4320 agaaatgtgg aactccagcc taagtatgaa gaaagtctgt acatgtatct ttactttgtt 4380 attttcatca tctttgggtc cttcttcacc ttgaacctgt ttattggtgt catcatagat 4440 aatttcaacc agcagaaaaa gaagtttgga ggtcaagaca tctttatgac agaagaacag 4500 aagaaatact ataatgcaat gaaaaaatta ggatcgaaaa aaccgcaaaa gcctatacct 4560 cgaccaggaa acaaatttca aggaatggtc tttgacttcg taaccagaca agtttttgac 4620 ataagcatca tgattctcat ctgtcttaac atggtcacaa tgatggtgga aacagatgac 4680 cagagtgaat atgtgactac cattttgtca cgcatcaatc tggtgttcat tgtgctattt 4740 actggagagt gtgtactgaa actcatctct ctacgccatt attattttac cattggatgg 4800 aatatttttg attttgtggt tgtcattctc tccattgtag gtatgtttct tgccgagctg 4860 atagaaaagt atttcgtgtc ccctaccctg ttccgagtga tccgtcttgc taggattggc 4920 cgaatcctac gtctgatcaa aggagcaaag gggatccgca cgctgctctt tgctttgatg 4980 atgtcccttc ctgcgttgtt taacatcggc ctcctactct tcctagtcat gttcatctac 5040 gccatctttg ggatgtccaa ctttgcctat gttaagaggg aagttgggat cgatgacatg 5100 ttcaactttg agacctttgg caacagcatg atctgcctat tccaaattac aacctctgct 5160 ggctgggatg gattgctagc acccattctc aacagtaagc cacccgactg tgaccctaat 5220 aaagttaacc ctggaagctc agttaaggga gactgtggga acccatctgt tggaattttc 5280 ttttttgtca gttacatcat catatccttc ctggttgtgg tgaacatgta catcgcggtc 5340 atcctggaga acttcagtgt tgctactgaa gaaagtgcag agcctctgag tgaggatgac 5400 tttgagatgt tctatgaggt ttgggagaag tttgatcccg atgcaactca gttcatggaa 5460 tttgaaaaat tatctcagtt tgcagctgcg cttgaaccgc ctctcaatct gccacaacca 5520 aacaaactcc agctcattgc catggatttg cccatggtga gtggtgaccg gatccactgt 5580 cttgatatct tatttgcttt tacaaagcgg gttctaggag agagtggaga gatggatgct 5640 ctacgaatac agatggaaga gcgattcatg gcttccaatc cttccaaggt ctcctatcag 5700 ccaatcacta ctactttaaa acgaaaacaa gaggaagtat ctgctgtcat tattcagcgt 5760 gcttacagac gccacctttt aaagcgaact gtaaaacaag cttcctttac gtacaataaa 5820 aacaaaatca aaggtggggc taatcttctt ataaaagaag acatgataat tgacagaata 5880 aatgaaaact ctattacaga aaaaactgat ctgaccatgt ccactgcagc ttgtccacct 5940 tcctatgacc gggtgacaaa gccaattgtg gaaaaacatg agcaagaagg caaagatgaa 6000 aaagccaaag ggaaataaat gaaaataaat aaaaataatt gggtgacaaa ttgtttacag 6060 cctgtgaagg tgatgtattt ttatcaacag gactccttta ggaggtcaat gccaaactga 6120 ctgtttttac acaaatctcc ttaaggtcag tgcctacaat aagacagtga ccccttgtca 6180 gcaaactgtg actctgtgta aaggggagat gaccttgaca ggagattact gttctcacta 6240 ccagctgaca ctgctgaaga taagatgcac aatggctagt cagactgtag ggaccagttt 6300 caaggggtgc aaacctgtga ttttggggtt gtttaacatg aaacacttta gtgtagtaat 6360 tgtatccact gtttgcattt caactgccac atttgtcaca tttttatgga atctgttagt 6420 ggattcatct ttttgttaat ccatgtgttt attatatgtg actatttttg taaacgaagt 6480 ttctgttgag aaataggcna aggacctcta taacangtat gccacctggg gggtanggca 6540 accacatggc nctcccagct acacaaagtc gtggtttgca tgagggcatg ctgcacttag 6600 agatcatgca tgagaaaaag tcacaagaaa aacaaattct taaatttcac catatttctg 6660 ggaggggtaa ttgggngata agtggaggtg ctttgttgat cttgttttgc gaaatccagc 6720 ccctanacca agtagattgt ttgtgggtag gncagtaaat cttagcaggt gcaaacttca 6780 ttcaaatgtt tggagtcata aatgttatgt ttctttttgt tgtattaaaa aaaaacctga 6840 atagtgaata ttgcccctca ccctccaccg ccagaagact gaattgacca aaattactct 6900 ttataaattt ctgctttttc ctgcactttg tttagccatc ttcggctctc agcaaggttg 6960 acactgtata tgttaatgaa atgctattta ttatgtaaat agtcatttta ccctgtggtg 7020 cacgtttgag caaacaaata acgacctaag cacagtattt attgcatcaa atatgtacca 7080 caagaaatgt agagtgcaag ctttacacag gtaataaaat gtattctgta ccatttatag 7140 atagtttgga tgctatcaat gcatgtttat attaccatgc tgctgtatct ggtttctctc 7200 actgctcaga atctcattta tgagaaacca tatgtcagtg gtaaagtcaa ggaaattgtt 7260 caacagatct catttattta agtcattaag caatagtttg cagcacttta acagcttttt 7320 ggttattttt acattttaag tggataacat aggtatatag ccagactgta cagacatgtt 7380 taaaaaaaca cactgcttaa cctattaaat atgtgtttag aattttataa gcaaatataa 7440 atactgtaaa aagtcacttt attttatttt tcagcattat gtacataaat atgaagagga 7500 aattatcttc aggttgatat cacaatcact tttcttactt tctgtccata gtactttttc 7560 atgaaagaaa tttgctaaat aagacatgaa aacaagactg ggtagttgta gatttctgct 7620 ttttaaatta catttgctaa ttttagatta tttcacaatt ttaaggagca aaataggttc 7680 acgattcata tccaaattat gctttgcaat tggaaaaggg tttaaaattt tatttatatt 7740 tctggtagta cctgtactaa ctgaattgaa ggtagtgctt atgttatttt tgttcttttt 7800 ttctgacttc ggtttatgtt ttcatttctt tggagtaatg ctgctctaga ttgttctaaa 7860 tagaatgtgg gcttcataat ttttttttcc acaaaaacag agtagtcaac ttatatagtc 7920 aattacatca ggacattttg tgtttcttac agaagcaaac cataggctcc tcttttcctt 7980 aaaactactt agataaactg tattcgtgaa ctgcatgctg gaaaatgcta ctattatgct 8040 aaataatgct aaccaacatt taaaatgtgc aaaactaata aagattacat tttttattcg 8100 aaaaaaggaa aaaaaaaaaa aaaaaaaaaa a 8131 14 6586 DNA Rattus norvegicus misc_feature (6539)..(6579) n is any nucleotide a, c, g, t (u) 14 ccaagatggc gcccaccgca gtcccgcccg ccgcagcctc ggcgcctctg cagtccggcc 60 gcgcctcccg ggccccgcgc tagggccgct gccgcctcgc ccgccgccgc cgccgccagc 120 tgacctgtcc cggacacata actaacgaag ctgctgcagg atgagaagat ggcagcgcgg 180 ctgctcgcac caccaggccc tgatagtttc aagcctttca cccctgagtc gctggcaaac 240 atcgagaggc gtattgccga gagcaagctc aagaaaccac caaaggcgga tggcagccac 300 cgggaggacg atgaagacag caagcccaag ccaaacagtg acctggaggc tgggaagagt 360 ttgcctttca tctacgggga catcccgcaa ggcctggttg cggttcccct ggaggacttt 420 gacccttact atttgacgca gaaaaccttt gtagtattaa acagagggaa aactctcttc 480 agatttagtg ccacacctgc cttgtacatt ttaagccctt ttaacctgat aagaagaata 540 gctattaaaa ttttgataca ctcagttttc agcatgatca tcatgtgcac catcctgacc 600 aactgtgtgt tcatgacctt tagtaaccct ccagaatggt ccaagaatgt ggagtacaca 660 ttcacaggga tttacacatt tgaatcacta gtgaaaatca tcgcaagagg tttctgcata 720 gacggcttca ccttcttgcg agacccgtgg aactggttag acttcagtgt catcatgatg 780 gcatatgtga cagagtttgt ggacctgggc aatgtctcag cgctgagaac attcagggtt 840 ctccgagctt tgaaaactat ctctgtaatt ccaggcctga agacaatcgt gggcgcccta 900 atccagtccg tgaagaagct gtcggacgtg atgatcctga cagtgttctg cctgagtgtt 960 ttcgccctga ttggcctgca gctcttcatg gggaaccttc gaaacaagtg tgtcgtgtgg 1020 cccataaact tcaacgagag ctacctggag aacggcacca gaggctttga ctgggaggaa 1080 tatatcaaca ataaaacaaa cttttacatg gttcctggca tgctagaacc cttgctctgc 1140 gggaacagtt ctgatgctgg gcaatgccca gagggattcc agtgcatgaa agcaggaagg 1200 aaccccaact acggttacac cagctttgac accttcagct gggccttctt ggcattattc 1260 cgccttatga cccaggacta ttgggagaac ttataccagc tgaccttacg agccgctggg 1320 aaaacgtaca tgatcttctt tgtcttggtc atcttcgtgg gttctttcta tctggtgaac 1380 ttgatcttgg ctgtggtggc catggcttat gaggaacaga accaggcaac actggaggag 1440 gcagagcaaa aagaggccga gttcaaggca atgctggagc aactcaagaa gcagcaggag 1500 gaggcacagg ctgctgcaat ggccacctca gcgggcactg tctcggaaga cgccattgaa 1560 gaagaagggg aagatggggt aggctctccg aggagctctt ctgaactgtc taaactcagt 1620 tccaagagcg cgaaggagcg gcggaaccga cggaagaaga ggaagcagaa ggagctctct 1680 gaaggcgagg agaaagggga cccggagaag gtgtttaagt cagagtcgga agacggtatg 1740 agaaggaagg ccttccggct gccagacaac aggataggga ggaagttttc catcatgaat 1800 cagtcgctgc tcagcattcc aggctcgccc ttcctctccc gacataacag caaaagcagc 1860 atcttcagct tccggggacc cggtcggttc cgggaccccg gctctgagaa tgagttcgca 1920 gacgatgaac acagcaccgt ggaggagagc gagggccggc gtgactcgct cttcatcccg 1980 atccgcgccc gcgagcgccg cagcagctac agtggctaca gcggctacag ccagtgcagc 2040 cgctcgtcgc gcatcttccc cagcctgcgg cgcagcgtga agcgcaacag cacggtggac 2100 tgcaacggcg tagtgtcact catcgggccc ggctcacaca tcgggcggct cctgcctgag 2160 gtgaaaatag ataaggcagc tacggacagc gcaacgactg aggtggaaat taagaagaaa 2220 ggccctggat ctcttttagt ttctatggac caactcgcct cctacggacg gaaggacaga 2280 atcaacagca taatgagcgt ggtcacaaac acgctagtgg aagagctgga agagtctcag 2340 agaaagtgcc caccgtgctg gtataagttt gccaacactt tcctcatctg ggagtgtcac 2400 ccctactgga taaaactgaa ggagatcgtg aacttaatcg tcatggaccc ttttgtagac 2460 ttagccatca ccatctgcat cgttctgaat acgctattta tggcaatgga gcaccatccc 2520 atgacaccac agttcgaaca cgtcttggcc gtaggaaatc tggtgttcac cgggatcttc 2580 acggcggaaa tgtttctgaa gctcatagcc atggacccct actattattt ccaagaaggc 2640 tggaacattt ttgacggatt tattgtctcc ctcagtttaa tggagctgag tctcgcagat 2700 gtggaggggc tctcagtgct gcggtctttc cgactgctcc gagtcttcaa gctggccaag 2760 tcctggccca ccctgaacat gctgatcaag atcatcggga actccgtggg tgccctgggc 2820 aacctgaccc tggtgctggc catcatcgtc ttcatcttcg ccgtggtggg gatgcagctg 2880 tttggaaaga gttacaagga gtgcgtctgt aagatcaacc aggagtgcaa gctcccgcgc 2940 tggcacatga acgacttctt ccactccttc ctcatcgtct tccgagtgct gtgtggggag 3000 tggatcgaga ccatgtggga ctgcatggag gtggccggcc aggccatgtg cctcattgtc 3060 ttcatgatgg ttatggtcat tggcaacctg gtggtgctga atctattcct ggccttgctt 3120 ctgagctcct tcagcgcaga caacctggcg gccacagacg acgacgggga aatgaacaac 3180 ctgcagatct cagtgatccg gatcaagaag ggcgtggcct ggaccaaagt gaaggtgcac 3240 gccttcatgc aggctcactt caagcagcgg gaggcggatg aagtgaaacc cctcgacgag 3300 ctgtatgaga agaaggccaa ctgcatcgcc aaccacacgg gcgtggatat ccaccggaac 3360 ggcgacttcc agaagaacgg gaacggaacc accagcggca tcggcagcag cgtggagaag 3420 tacatcatcg acgaggacca catgtccttc attaacaacc caaacctgac cgtccgggtg 3480 cccattgctg tgggcgagtc tgacttcgag aacctcaaca cagaggatgt tagcagcgaa 3540 tcagaccctg aaggcagcaa agataaactg gacgatacca gctcctcaga aggaagtacc 3600 atcgacatca agcctgaggt ggaagaagtt cccgtggagc aacctgagga atacttggat 3660 ccggacgcct gctttacaga gggttgcgtc cagcggttca agtgctgcca ggtcaacatc 3720 gaggaaggac taggcaagtc gtggtggatc ttgcggaaaa cctgcttcct cattgtggag 3780 cacaattggt ttgagacctt catcatcttc atgattctgc tcagcagtgg cgccctggcc 3840 tttgaggaca tctacattga gcagaggaag accatccgca ccatcctgga gtatgcggac 3900 aaggtcttca cctacatctt catcctggag atgttgctca agtggacagc ctacggcttc 3960 gtcaagttct tcaccaatgc ctggtgctgg ttggacttcc tcattgtggc tgtctcttta 4020 gtcagcctta tagctaatgc cctgggctac tcggaactag gtgccataaa gtcccttagg 4080 accctaagag ctttgagacc cttaagagcc ttatcacgat ttgaagggat gagggtggtg 4140 gtgaatgcct tggtgggcgc catcccctcc atcatgaatg tgctgctggt gtgtctcatc 4200 ttctggctga ttttcagcat catgggagtt aacctgtttg cggggaaata ccactactgc 4260 tttaatgaga cttctgaaat ccggttcgaa atcgatattg tcaacaataa aacggactgt 4320 gagaagctca tggagggcaa cagcacggag atccgatgga agaatgtcaa gatcaacttt 4380 gacaatgtcg gagcagggta cctggccctt cttcaagtgg caaccttcaa aggctggatg 4440 gacatcatgt atgcggctgt agattcccga aagccagacg agcagcctga ctacgagggc 4500 aacatctaca tgtacatcta cttcgtcatc ttcatcatct tcggctcctt cttcaccctc 4560 aacctgttca tcggtgtcat catcgacaac ttcaaccagc agaagaaaaa gtttggaggt 4620 caggacatct tcatgacaga ggaacagaag aagtactaca atgccatgaa aaagctgggc 4680 tccaagaagc cacagaagcc catcccccga cccttgaaca aaatccaagg gattgtcttt 4740 gatttcgtca ctcaacaagc ctttgacatt gtgatcatga tgctcatctg ccttaacatg 4800 gtgacaatga tggtggagac agacactcag agcaagcaga tggagaacat tctttactgg 4860 attaatctgg tctttgtcat cttcttcacc tgcgagtgtg tgctcaaaat gtttgccttg 4920 agacactact atttcaccat tggctggaac atctttgact ttgtggtggt catcctctcc 4980 attgtgggaa tgttcctggc tgatatcatt gagaagtact tcgtctcccc aaccctattc 5040 cgagttatcc gattggcccg tattgggcgc atcttgcgtc tgatcaaggg cgccaaaggg 5100 atccgcaccc tgctctttgc cttaatgatg tcgctgcccg ccctgttcaa catcggcctc 5160 ctgctcttcc tcgtcatgtt catcttctcc atttttggca tgtccaactt cgcatacgtg 5220 aagcacgagg ccggcattga cgacatgttc aacttcgaga catttggcaa cagcatgatc 5280 tgtttgttcc agatcacaac gtctgctggc tgggatggcc tgctgctgcc aatcctgaac 5340 cgcccccctg actgcagctt ggacaaagag cacccaggga gtggcttcaa aggggactgt 5400 gggaacccct cggtgggcat cttcttcttt gtgagctaca tcatcatctc cttcctgatt 5460 gtggtgaaca tgtacatcgc catcatcctg gagaacttca gcgtggccac cgaggagagc 5520 gccgaccctc tgagtgagga tgacttcgag actttctatg agatctggga gaagtttgac 5580 ccagacgcca cccagttcat cgagtactgt aagctggcag actttgccga cgccctggag 5640 cacccgctcc gagtacccaa gcccaacacc atcgagctca tcgccatgga cctgcccatg 5700 gtgagcggag atcgcatcca ctgcttggac atccttttcg ccttcaccaa gcgagtcctg 5760 ggagacagtg gggagttgga catcctgcgg cagcagatgg aggagcggtt cgtggcatcc 5820 aatccttcca aagtgtctta cgagcctatc acaaccactc tgcggcgcaa gcaggaggag 5880 gtgtctgcag tggtcctgca gcgtgcctac aggggacact tggctaggcg gggcttcatc 5940 tgcagaaaga tggcctccaa caagctggag aatggaggca cacacagaga caagaaggag 6000 agcaccccgt ccacagcctc cctcccctct tacgacagcg tcacaaagcc agacaaggag 6060 aagcagcagc gtgcggagga gggcagaagg gaaagagcca agaggcaaaa agaggtcagg 6120 gagtccaagt gctagaggag gggaaaggaa gcttaccccg gctgaacact ggcaagtgaa 6180 agcttgttta caaacttccg aatctcacgg atgcagagca gctgtgcaga cgctcgctgt 6240 actggaagac ctataccaaa catagtctgc ttacatgtga catggtggca tcctgagcgg 6300 tgactgctgg ggacaaagga ccctgctccc tggactcaca gatctcctat cgcttgggca 6360 gacggttact gcatgttcca cacttagtca atgcaactta ggactaaact aaccaggata 6420 caaaaccgag gcggctgccg ggaccagcag atcaccgctg cagccaaatg gattttattt 6480 tttcattttg ttgattctca gaagcagaaa gcatcacttt aaaagtttgt ttgttcatnc 6540 aaacaatatt tgaattctta cattagttaa gctaagcanc aaaaag 6586 15 5858 DNA Mus musculus 15 tggtgccctg agcctcccta gcaggaagac agtgtctgag ccaagggtga agatggagga 60 gaggtactat ccagtgatct tcccagacga gaggaatttc cgccccttca ctttcgactc 120 tttggctgca atagagaagc ggatcaccat ccaaaaggag aagaagaaat ccaaagacaa 180 ggcagcaact gagccccagc ctcggcctca gctcgaccta aaggcctcca ggaagttacc 240 taagctctat ggcgacgttc cccctgacct tatagcgaag cccctggaag atctggaccc 300 attttacaaa gaccataaga cattcatggt attgaacaag aagagaacaa tctatcgctt 360 cagcgccaag agggccttgt tcattctggg gccttttaat cccatcagaa gcttcatgat 420 tcgcatctct gtccattcag tcttcagcat gttcattatc tgcacagtga tcatcaactg 480 tatgttcatg gctaataatt cttctgtgga cagtcgtcct agcagtaaca ttcccgaata 540 cgtcttcatt gggatttatg ttttagaagc tgtgattaaa atattggcaa gaggcttcat 600 tgtggatgag ttttcctacc tccgagatcc ttggaactgg ctggacttca ttgtcatcgg 660 aacagcgata gcgccttgtt ttctcggtaa caaagtcaat aatctttcca ctctacgtac 720 cttccgagtg ttgagagctc tgaaagccat ttctgtaatc tcaggtctga aggtcatcgt 780 gggtgccctg ctgcgctccg tgaagaagct agtggacgtg atggtcctca ctctcttttg 840 cctcagcatc tttgccctgg ttggtcagca gctcttcatg ggaattctga gccagaaatg 900 tattaaggac gactgtggcc ctaacgcttt ttccaacaag gattgctttg taaaagaaaa 960 tgatagcgag gacttcataa tgtgtggcaa ctggctcggc agaagatcct gccccgatgg 1020 ttccacgtgc aataaaacca catttaaccc agattataat tatacaaact ttgacagctt 1080 tggctggtct tttctcgcca tgttccgggt tatgactcaa gactcctggg agaagcttta 1140 tcgacagatc cttcgcacct ccgggatcta ctttgtcttc ttcttcgtgg tcgtcatctt 1200 cctgggctct ttctacctgc ttaacttaac cctggctgtc gtcaccatgg cttacgagga 1260 acagaacaga aatgtcgctg ccgagacaga ggccaaggag aagatgtttc aggaagccca 1320 gcagctgttg agggaggaaa aggaggctct ggttgccatg ggaattgaca gaacttccct 1380 taattccctc caagcttcgt ccttttcccc aaagaagagg aagttttttg gcagtaagac 1440 aagaaagtcc ttctttatga gagggtccaa gacagcccga gcctcagcgt ccgattcaga 1500 ggacgatgcc tctaaaaacc cacaactcct tgagcaaaca aaacgactat cccagaactt 1560 gcccgtagaa ctctttgatg agcacgtgga ccccctccat aggcagagag cgctgagtgc 1620 cgtcagtatc ttaaccatca ccatgcagga acaagaaaaa tcccaggagc cttgtttccc 1680 gtgtgggaaa aacttggcat ccaagtacct ggtgtgggaa tgtagccctc cgtggctgtg 1740 cataaagaag gtcctgcaga ctatcatgac agaccccttc actgagctgg ccatcaccat 1800 ctgcatcatc gtcaatactg tcttcttggc catggaacac cacaatatgg ataactcttt 1860 aaaagacata ctgaaaatag gaaactgggt tttcactgga attttcatag cggaaatgtg 1920 tctcaagatc attgcgctag acccttacca ctacttccgg cacggctgga acatctttga 1980 cagcattgtg gcccttgtga gtctcgctga cgtgctcttc cacaaactgt ctaaaaacct 2040 ctccttcttg gcttccctca gagtgctgag ggtcttcaag ttagccaaat cctggcccac 2100 attaaacact ctcattaaga tcatcggcca ctccgtgggt gcgctcggaa acctgactgt 2160 ggtcctaacg atcgtggtct tcatcttttc cgtggttggc atgcggctct ttggtgccaa 2220 gtttaacaag acttgctcca cctctccgga gtccctccgg cgctggcaca tgggtgattt 2280 ctaccattcc ttcctggtgg tgttccgcat cctctgtggg gagtggatcg agaacatgtg 2340 ggaatgcatg caggagatgg aaggctcccc gctgtgtgtc atcgtctttg tgctgatcat 2400 ggtggtcggg aagctcgtgg tgcttaacct cttcattgcc ttgctgctca attccttcag 2460 caatgaggaa aaggatggga acccagaagg agagaccagg aaaaccaaag tgcagctagc 2520 cctggatcgg ttcagccgag cgttctactt catggcgcgc gctcttcaga atttctgttg 2580 caagagatgc aggaggcaaa actcgccaaa gccaaatgag gcaacagaaa gctttgctgg 2640 tgagagtaga gacacagcca ccctggatac aaggtcctgg aaggagtatg attcagaaat 2700 gactctgtac actgggcagg ccggggctcc actggcccca ctggcaaaag aagaggacga 2760 tatggaatgt tgtggtgaat gtgatgcctc acctacctca cagcctagtg aggaagctca 2820 ggcctgtgac ctccctctga agaccaagcg gctccccagc ccagatgacc acggggttga 2880 aatggaagtg ttttccgaag aagatccgaa tttaaccata cagagtgctc gaaagaagtc 2940 tgatgcggca agcatgctct cagaatgcag cacaatagac ctgaatgata tctttagaaa 3000 tttacagaaa acagtttccc cccaaaagca accagatcga tgctttccca agggcctcag 3060 ttgtatcttt ctatgttgca aaacaatcaa aaaaaagtcc ccctgggtcc tgtggtggaa 3120 tcttcggaaa acctgctacc aaatcgtgaa gcatagctgg tttgagagct tcataatttt 3180 tgtcatcctg ctgagcagcg gagcactgat attcgaagat gtcaatcttc ccagccggcc 3240 ccaagttgaa aaattactga agtgtaccga taatattttc acatttattt ttctcctgga 3300 aatgattttg aagtgggtgg cctttggatt ccggaagtat ttcaccagtg cctggtgctg 3360 gctcgatttc ctcattgtgg tggtgtctgt gctcagcctc acgaacttac caaacttgaa 3420 gtccttccgg aatctgcgag cgctgagacc tctgcgggca ctgtctcagt ttgaaggaat 3480 gaaggttgtt gtcaatgccc tcatgagtgc catacctgcc atcctcaatg tcttgctggt 3540 ctgcctcatt ttctggctca tattttgtat cctgggagta aatttttttt ctgggaagtt 3600 tggaagatgc attaatggaa cagacataaa taaatatttc aacgcttcca atgttccaaa 3660 ccaaagccaa tgtttagtta gtaattacac gtggaaagtc ccgaatgtca actttgacaa 3720 cgtggggaat gcctaccttg ccctgctgca agtggcgacc tataagggct ggctggacat 3780 tatgaatgca gctgttgatt ccagagggaa agatgagcag ccggcctttg aggcgaatct 3840 atacgcatac ctttacttcg tggtttttat catcttcggc tcattcttta ccctgaacct 3900 ctttatcggt gttattattg acaacttcaa tcagcagcag aaaaagttag gtggccaaga 3960 catttttatg acagaagaac agaagaaata ttacaatgca atgaaaaagt taggaaccaa 4020 gaagcctcaa aagcccatcc caaggcccct gaacaaatgt caagccttcg tgttcgattt 4080 ggtcacaagc caggtctttg acgtcatcat tctgggtctt attgtcacaa acatgattat 4140 catgatggct gaatctgaag gccagcccaa cgaagtgaag aaaatctttg atattctcaa 4200 catagtcttc gtggtcatct ttaccgtaga gtgtctcatc aaagtctttg ctttgaggca 4260 acactacttc accaatggct ggaacttatt tgattgtgtg gtcgtggttc tttccatcat 4320 tagtaccttg gtttctggct tggagaacag caacgtcttc ccgcccacac tcttcaggat 4380 tgtccgcttg gctcggatcg gtcgaatcct cagactggtc cgggcggctc gaggaatcag 4440 gacactcctt ttcgcgttga tgatgtctct cccctctctc ttcaacattg gtctgcttct 4500 ctttctggtg atgttcattt atgccatctt tgggatgaac tggttttcca aagtgaagag 4560 aggctctggg attgatgaca tcttcaactt tgacactttc tcgggcagca tgctctgcct 4620 cttccagata accacttcag ccggctggga tgctctcctc aaccccatgc tggaatcaaa 4680 agcctcttgc aattcctcct cccaagagag ctgtcagcag ccgcagatag ccatagtcta 4740 cttcgtcagc tacatcatca tctcctttct cattgtggtt aacatgtaca tagctgtgat 4800 tctagagaac ttcaacacag ccacagagga gagcgaggac cccctgggcg aagacgactt 4860 tgagatcttc tatgagatct gggagaagtt tgaccccgaa gcaacacagt tcatccagta 4920 ctcatccctc tctgacttcg ccgacgccct gcccgagccg ttgcgtgtgg ccaagcccaa 4980 caggtttcag tttctcatga tggacttgcc catggtgatg ggtgatcgcc tccattgcat 5040 ggatgttctc tttgctttca ccaccagggt cctcgggaac tccagcggct tggataccat 5100 gaaagccatg atggaggaga agttcatgga ggccaatcct ttcaagaagt tgtacgagcc 5160 cattgtcacc accacaaaga ggaaggagga ggaggaatgt gccgctgtca tccagagggc 5220 ctaccggaga cacatggaga agatgatcaa gctgaagctg aaaggcaggt caagttcatc 5280 gctccaggtg ttttgcaatg gagacttgtc tagcttggat gtgcccaaga tcaaggttca 5340 ttgtgactga aacccccacc tgcacgccta cctcacagcc tcacagctca gcccccagcc 5400 tctggcgaac aagcggcgga ctcaccgaac aggccgttca acttgttttt ttgggtgaaa 5460 gaggtgatag gttggtgtcc atttttaaat gattcttgga aagattgaac gtcggaacat 5520 gttagaaagg actgccaagg acatccacag taacggaagg cctgaaggac agttcaaatt 5580 atgtaaagaa acgagaagga aaggtcacat gtctgttcag ttttaagtat gtgacctgcc 5640 acatgtagct cctttgcatg ttaagtgaga agtcaaaacc ctgccataag taaatagctt 5700 tgttgcaggt gtttctacca gtgctgccga tttgggtgta tggctcaaac ctgaaagcat 5760 gactctgact tgtcagcacc ccaactttca gaagctctga tctctgtcct aggtgtttga 5820 caaataaata cataaaaaaa aaaaaaaaaa aaaaaaaa 5858 16 6503 DNA Bos Taurus 16 cgggacccgg gccgggggac cagcagcttc ccttcaggca gcgtgaggac agcctgtgcc 60 ccagaagcag gatgagaaga tggcagcctt cctgttacct cggggcacca gcagcttccg 120 caggttcacc cgggagtctc tggcggccat cgagaagcgc atggcagaga agcaggcccg 180 gagctcggcc gcctcgcagg agagccgcga cgggctgccc gaggaggagg cgccccggcc 240 ccagctggac ctgcaagcct ccaaaaagct gccggatctc tacggcaacc caccccgaga 300 gctcatcggg gagcccctgg aggacctgga ccccttctat agcactcaaa agaccttcat 360 cgtcctgaac aaaggcaaga ccatcttccg gttcagcgcc accaacgcct tgcatgtcct 420 cagccccttc caccccatcc ggagagtggc tgtgaagatc ttggtgcatt cgctcttcag 480 catgctcatc atgtgtacca ttctgaccaa ctgcgtgttc atggcccagc acgaccctcc 540 gccctggacc aaatatgtcg agtacatctt cactgccatc tacacctttg agtctctggt 600 caagattctg gctcgaggct tctgcctgca cgcgttcacc ttccttcggg acccgtggaa 660 ctggctggac ttcagcgtga tcatcatggc atacaccact gaatttgtgg acctgggcaa 720 tgtctcagct ttacgtacct tccgagtcct ccgggccctg aaaactatat cagtcatttc 780 aggcctgaag accatcgtgg gggccctgat ccagtctgtg aagaagctgg ccgatgtgat 840 ggtcctcacg gtcttctgcc tcagcgtctt cgccctcatc ggccttcagc tcttcatggg 900 caacctgagg cacaagtgcg tccgcaactt cacggtgctc aacggcacca acagcaccaa 960 tgcctccgtg gaggccgacg gcctgatctg ggcatcgctg gacgactacc tcaacgaccc 1020 agaaaattac ctactcaaga atggcacctc tgacgtgtta ctgtgtggga acagctccga 1080 cgctgggaca tgtcctgagg gctacaggtg cctgaaggca ggtgggaacc ctgaccatgg 1140 ctacaccagc ttcgactcct tcgcctgggc cttcctcgca ctcttccgac tgatgacgca 1200 ggactgctgg gagcgcctct accagcagac cctgaggtct gcagggaaga tctacatgat 1260 cttcttcatg ctggtcatct tcctgggctc cttctacttg gtgaacttga tcctggctgt 1320 ggtcgccatg gcctacgagg agcaaaacca agccaccatc gcagagacag aggagaagga 1380 aaagcgattc caggaagcca tggagttgct caagaaagag caggaggccc tcgccatcag 1440 gggtgtggac accgtgtccc gcagctcctt ggagatgtcc ccattggccc cagtaaccac 1500 ccacgagaga aggagcaaga gaagaaaacg aatgtcttca gggatggaag agtgtgggga 1560 cgacaagttc cccaagtccg actcagagga tggtccccga gcagtgaatc gtttcagcat 1620 cacccatggc ctcagcagga cctccatgaa gccgcgctcc agccacggga gcattttcac 1680 cttccgccga cgggacctgg gctccgagac agattttgcg gacgatgaaa acagcaccgc 1740 cggggacagt gagagccacc gcacatcact gctggtgcct tggcccctgc ggcggcctag 1800 taccctggga cagcccagtc ccggaacctc aactcccggc cacgtgctca acggcaaaag 1860 gaacagcact gtggactgta acggggtggt ctccttgctg ggggcaggag accccgaggc 1920 cacctcccca gggagtcacc tcctccaccc tatgaagctg gagcgccccc cagacacgac 1980 cacaccatcg gaggagccgg gcaggcccca gacgctgacg ccccaggctc cgtgtgtaga 2040 cggcttcgag gagccaggag agcggcagcg agccctcagt gcagtgagcg tcctcaccag 2100 tgccctggaa gagctggagg agtctcagcg caggtgtcca ccgtgctgga tccgttttgc 2160 ccagcactac ctgatctggg agtgctgccc gctgtggatg tccattaagc agaaagtgaa 2220 gttcatggtc atggacccat ttgctgacct caccatcacc atgtgcatcg tgcttaacac 2280 gctcttcatg gcactggagc actacaacat gacgaccgaa tttgaggaga tgctgcaggt 2340 tggaaacctg gtcttcacag gaatattcac agcagagatg accttcaaga tcattgcctt 2400 ggacccctac tactacttcc agcagggctg gaacatcttc gacagcatca tcgtcatcct 2460 cagcctcatg gagctgggcc tgtcccgcat gggcaatctg tcggtgcttc gctccttctg 2520 cctgcttcgg gtcttcaagc tggccaagtc ctggcccacc ctgaacacac tcatcaagat 2580 cattgggaac tcagtgggcg cgctaggcaa cctgacgttg gtgctggcca tcattgtgtt 2640 catcttcgct gtggtgggca tgcagctctt tggcaagaac tactcagagc agaggcaccg 2700 tatcagtgac tcgggcctcc tgccccgctg gcacatgatg gacttcttcc atgccttcct 2760 catcatcttc cgcatcctct gtggagagtg gatcgagacc atgtgggact gcatggaggt 2820 gtctgggcag tcactatgcc tgctggtctt cctgcttgtt atggtcattg gtaacctcgt 2880 ggtcctgaac ctcttcctgg ctttactgct cagctccttc agcgcagaca acctcacagc 2940 tcccgacgag gatggggaga tgaacaacct ccagctggct ctggcccgca tccagcgagg 3000 cctgcgcttc atcaagcgga ccacctggga cttctgctgc gtgctcctgc agcggccgcc 3060 tcagaagccc gcggccctcg cctcccaggg ccagctgccg ggctgtatcg ccacctccag 3120 ccccccaccc caaccagaga gcgagaaggc gcccccagcc cgcaaggaga cgcggtttga 3180 ggaaggccag cggccaggtc agggcgcacc tggggatgcc gagcctgtgt gtgtgcccat 3240 cgccgtggcc gagtcagaca cggatgaccc cgaggaggat gaggagaaca gcctaagcac 3300 agaggaagag tccagcaagc agcaggaatc ccagctggcg tccggcagcc cagaggccct 3360 cccagagccg agggtctgga gccaggtgtc ggagaccacc tcctctgggg ccgaggccag 3420 tgaggttcag gcagacttgc ggcagcagcg gcgagcagag gcccccgccc cagggtgcag 3480 tgagcttccc gaagacagtt actctgaggg gagcacggca gatatgacca acactgctga 3540 cctcctggag cagatccctg acctcggaga ggatgtcaaa gatccagagg actgcttcac 3600 tgaaggctgt gtccgccgct gtccctgctg caccgtggac accacacagg cccacgggaa 3660 ggtctggtgg aggctgcgca agacctgcta ccgcatcgtg gagcacagct ggttcgagac 3720 gttcatcatc ttcatgatcc tgctcagcag tggcgcactg gcctttgagg acatctacct 3780 ggaggagcgg aagaccatca aggtcctgct ggagtacgcc gacaagatgt tcacctacgt 3840 cttcgtgctg gagatgctcc tcaagtgggt ggcctacggc ttcaagaagt acttcaccaa 3900 cgcctggtgc tggcttgatt tcctcatcgt ggacgtcttg ctgatcagcc tggtggccaa 3960 cgccctgggc tttgctgaga tgggccccat caagtcactg cggaccttgc gtgcgctcag 4020 acccctgcga gccctgtcac gatttgaggg catgagggtt gtggttaacg ccctggtggg 4080 cgccatccca tccatcatga acgtcctcct cgtctgcctc atcttctggc tcatcttcag 4140 catcatgggc gtgaacctct tcgcggggaa gtttgggaga tgcatcaacc agaccgaggg 4200 agacctgccc ttgaactata ccatcgtgaa caacaagagc gactgtgagt ctttcaatgt 4260 gactggcgaa ttgtactgga ccaaggtgaa ggtcaacttt gacaacgtgg gggccgggta 4320 cctggccctt ctgcaggtgg caacatttaa aggctggatg gacatcatgt atgcagctgt 4380 agactccagg gggtacgagg agcagcccca gtgggaatac aacctctaca tgtatatcta 4440 ttttgtcatc ttcatcatct ttgggtcttt cttcaccctg aacctgttca tcggtgtcat 4500 cattgacaac ttcaaccagc agaagaaaaa gttagggggc caggacatct tcatgacaga 4560 ggagcagaag aagtactaca acgccatgaa gaagctgggc tccaagaagc cccagaagcc 4620 catcccacgg cccctgaaca agtaccaggg cttcatattc gacattgtga ccaagcaggc 4680 cttcgacgtc accatcatgt ttctcatctg cttaaacatg gtgaccatga tggtggagac 4740 agacgaccag agccccgaga aggtcaacat cttggccaag atcaacctgc tgttcgtggg 4800 catcttcaca gccgagtgta tcttcaagat ggttgccctg cgccactatt acttcaccaa 4860 cagctggaac atcttcgact tcgtggttgt catcctctcc atcgtaggca ctgtgctctc 4920 agacatcatc cagaagtact tcttctcccc gacgctcttc cgcgtcatcc gcctggcccg 4980 catcagccgc atcctcaggc tgatccgcgg ggccaagggc atccgcacgc ttctcttcgc 5040 cctcatgatg tccctgcccg cgctcttcaa catcgggctg ctgctcttcc tcgtcatgtt 5100 catctactcc atcttcggca tggccaactt cgcctacgtc aagtgggagg ctggcatcga 5160 cgacatgttc aacttccaga ccttcgccaa cagcatgctg tgcctcttcc agatcaccac 5220 gtcggcgggc tgggatgggc tcctcagccc catcctcaac acggggcccc cctactgcga 5280 ccccaacctg cccaacagca acggctcccg gggcaactgc gggagccccg cggtgggcat 5340 cctcttcttc accacctaca tcatcatctc cttcctcatt gtggtcaaca tgtacatcgc 5400 catcatcctg gagaacttca gcgtggccac ggaggagagc acggagcccc tgagtgagga 5460 tgacttcgac atgttctacg agatctggga gaagttcgac ccggaggcca cccagttcat 5520 cgagtatttg gccctgtctg acttcgccga tgccctgtca gagccactcc ggatccccaa 5580 gcccaaccag ataagcctca tcaatatgga cctgcccatg gtgagtggag accgcatcca 5640 ctgcatggac atcctctttg ccttcaccaa gagggtcctg ggcgaatctg gggagatgga 5700 cgccctgaag atccagatgg aggagaagtt catggcggcc aacccgtcca agatctccta 5760 cgagcccatc accaccacgc tgcggcggaa gcacgaggag gtgtcggcca cgatcatcca 5820 gcgggccttc cgccggcacc tgctgcagcg ctccgtcaag cacgcctcct tcctctaccg 5880 ccagcaggcg ggcagcagcg gcctctcgga ggaggacgcc cccgagcagg agggcctcat 5940 cgcctacatg atgaacgaga acttctcccg ccgccccggc ccgccctcca gctcctccgt 6000 ctcctccacg tccttcccgc cctcctacga cagcgtcacc agggccacca gcgacaaccc 6060 ccaggtgcgg gcgtctgact acagcccaag cgaggatctc gccgacttcc ccccaacccc 6120 cgacagggac cgtgagtcaa tcgtgtgagc gcagcccagg ggaggggggc gccagcgcag 6180 agcatcgcgg caaacccaaa ggcagcccca gcccagcagt cgctgggccg tccgaccttt 6240 gctttgggct tcgggagtga gaggagcctc ggccccgtgg accgacaagg cagagtcctg 6300 tgcaccgcgc tgatggctgg aagcacttgg ccgagctgtc tgtctggggt taccagtcct 6360 gggggctggg tctggtccgg caacgctctg gggctctgac caccacctcc atcccagctg 6420 ctgaggcaaa atgcgaaacc gagactgtgt atgttgtgaa tgggctttca taaatttatt 6480 atatttgaaa aaaaaaaaaa aaa 6503 17 2732 DNA D. melanogaster 17 gcgacgactg tcgtcagtca gtcaatcaat cagtcagtca gtcagtcagt ccgtcagtca 60 gtcggtcagt cagttagtca gccagctagt cagttagcta gtcattcatt cagtcagtca 120 atcagtcagt gtgtcaatct gacaattgga gtttctatcc agacttcaat atttttttac 180 ctcgctcaaa accccccact cgcactttaa ataataaaaa aaagcaggtg gtgcgtgccg 240 cgtagccgcg cgtgattctt gttgttgttt tttttttttc ggtgaatctc ttgtaaccat 300 gtaccaaagt tctttgccgc gaaaactaaa atgaaaacga aagtgaaaat gagcgaatgg 360 cagccgcggc cacagcaatc gatccatgac acaaccagtg acaagcagtc ccccagtgaa 420 accgcatccg catccgagtc cgataccgat aaagattctg aatcggagtg agtgccgcgt 480 ccgagagcgt tccctgtcca cgtccaccat cggcggagca ggtgtgcctg aggcccacct 540 ggtggcatgg ccgccgttgc cggcctctat ggccttgggg aggatcgcca gcaccgcaag 600 aagcagcagc aacagcagca gcaccagaag gagcagctcg agcagaagga ggagcaaaag 660 aagatcgccg agcggaagct gcagctgcgg gagcagcagc tccagcgcaa ctccctcgat 720 ggttacgggt ctttgcccaa attgagcagt caagacgaag aagggggggc tggtcatggc 780 tttggtggcg gaccgcaaca ctttgaaccc attcctcacg atcatgattt ctgcgaaaga 840 gtcgttataa atgtaagcgg attaaggttt gagacacaac tacgtacgtt aaatcaattc 900 ccggacacgc tgcttgggga tccagctcgg agattacggt actttgaccc gcttagaaat 960 gaatattttt ttgaccgtag tcgaccgagc ttcgatgcga ttttatacta ttatcagagt 1020 ggtggccgac tacggagacc ggtcaatgtc cctttagacg tatttagtga agaaataaaa 1080 ttttatgaat taggtgatca agcaattaat aaattcagag aggatgaagg ctttattaaa 1140 gaggaagaaa gaccattacc ggataatgag aaacagagaa aagtctggct gctcttcgag 1200 tatccagaaa gttcgcaagc cgccagagtt gtagccataa ttagtgtatt tgttatattg 1260 ctatcaattg ttatattttg tctagaaaca ttacccgaat ttaagcatta caaggtgttc 1320 aatacaacaa caaatggcac aaaaatcgag gaagacgagg tgcctgacat cacagatcct 1380 ttcttcctta tagaaacgtt atgtattatt tggtttacat ttgaactaac tgtcaggttc 1440 ctcgcatgtc cgaacaaatt aaatttctgc agggatgtca tgaatgttat cgacataatc 1500 gccatcattc cgtactttat aacactagcg actgtcgttg ccgaagagga ggatacgtta 1560 aatcttccaa aagcgccagt cagtccacag gacaagtcat cgaatcaggc tatgtccttg 1620 gcaatattac gagtgatacg attagttcga gtatttcgaa tatttaagtt atctaggcat 1680 tcgaagggtt tacaaatatt aggacgaact ctgaaagcct caatgcggga attaggttta 1740 cttatatttt tcttatttat aggcgtcgta ctcttctcat cggcggttta ttttgcggaa 1800 gctggaagcg aaaattcctt cttcaagtcc atacccgatg cattttggtg ggcggtcgtt 1860 accatgacca ccgttggata tggtgacatg acacccgtcg gcgtttgggg caagattgtg 1920 ggatcacttt gtgccattgc tggcgtgctg accatcgcac tgccggtgcc ggtcatcgtc 1980 agcaatttca actacttcta tcaccgcgaa acggatcagg aggagatgca gagccagaac 2040 tttaatcacg ttactagttg tccatatttg ccaggtacat taggtcaaca catgaagaaa 2100 tcatcattgt ctgagtcctc atcggatatg atggatttgg acgatggtgt cgagtccacg 2160 ccgggattga cagaaacaca tcctggacgc agtgcggtgg ctccattttt gggagcccag 2220 cagcagcagc aacaacaacc ggtagcatcc tcgctgtcga tgtcgatcga caaacaactg 2280 cagcacccac tgcagcacgt gacgcagacg caactgtacc aacagcagca acagcagcag 2340 cagcagcagc aaaacggctt caagcagcag cagcaacaga cgcagcagca gctgcaacag 2400 caacagtccc acacaataaa cgcaagtgca gcagcggcga cgagcggcag cggcagtagc 2460 ggtctcacca tgaggcacaa taatgccctg gccgttagta tcgagaccga cgtttgacta 2520 ctggtgcaaa agacgttgcg tggtataaat ttggccttga caggagttac gttggatgcc 2580 agaaacgact acaaaagctg tttatattta atttaagtag aacaaataac aaaaacaaat 2640 ttaatctatt gctaaattaa attaaaatct aaattaaaat ctaaattaat ttaattaaat 2700 tatagattta atgataaaca acactaaaaa aa 2732 18 3756 DNA Homo sapiens 18 gtcgggatgg aggtgagaag acggccgtga cgcgcgcccg cggggccccc tgcaccccca 60 gcagcccaca gcgctccctg cccccctccc ccgcagcagc gggccttgcc gtcgagtgac 120 agcggcctgg gggggcaggg ggggcggggg cggccggatc agcgatgccg gcgggcatga 180 cgaagcatgg ctcccgctcc accagctcgc tgccgcccga gcccatggag atcgtgcgca 240 gcaaggcgtg ctctcggcgg gtccgcctca acgtcggggg gctggcgcac gaggtactct 300 ggcgtaccct ggaccgcctg ccccgcacgc ggctgggcaa gctccgcgac tgcaacacgc 360 acgactcgct gctcgaggtg tgcgatgact acagcctcga cgacaacgag tacttctttg 420 accgccaccc gggcgccttc acctccatcc tcaacttcta ccgcactggg cgactgcaca 480 tgatggagga gatgtgcgcg ctcagcttca gccaagagct cgactactgg ggcatcgacg 540 agatctacct ggagtcctgc tgccaggccc gctaccacca gaagaaagag cagatgaacg 600 aggagctcaa gcgtgaggcc gagaccctac gggagcggga aggcgaggag ttcgataaca 660 cgtgctgcgc agagaagagg aaaaaactct gggacctact ggagaagccc aattcctctg 720 tggctgccaa gatccttgcc ataatttcca tcatgttcat cgtcctctcc accattgccc 780 tgtccctcaa cacgctgcct gagctacaga gcctcgatga gttcggccag tccacagaca 840 acccccagct ggcccacgtg gaggccgtgt gcatcgcatg gttcaccatg gagtacctgc 900 tgaggttcct ctcctcgccc aagaagtgga agttcttcaa gggcccactc aatgccattg 960 acttgttggc cattctgcca tactatgtca ccattttcct caccgaatcc aacaagagcg 1020 tgctgcaatt ccagaatgtc cgccgcgtgg tccagatctt ccgcatcatg cgaattctcc 1080 gcatccttaa gcttgcacgc cactccactg gcctccagtc tctgggcttc actttgcgga 1140 ggagctacaa tgagttgggc ttgctcatcc tcttccttgc catgggcatt atgatcttct 1200 ccagccttgt cttctttgct gagaaggatg aggacgacac caagttcaaa agcatcccag 1260 cctctttctg gtgggccacc atcaccatga ctactgttgg gtatggagac atctacccca 1320 agactctcct ggggaaaatt gttgggggac tctgctgcat tgcaggagtc ctggtgattg 1380 ctcttcccat ccccatcatc gtcaataact tctctgagtt ctataaggag cagaagagac 1440 aggagaaagc aatcaaacgg cgagaggctc tggagagagc caagaggaat ggcagcatcg 1500 tatccatgaa catgaaggat gcttttgccc ggagcattga gatgatggac attgtggttg 1560 agaaaaatgg ggagaatatg ggtaagaaag acaaagtaca agataaccac ttgtctccta 1620 acaaatggaa atggacaaag aggacactgt ctgaaaccag ctcaagtaag tcctttgaaa 1680 ccaaggaaca gggatcccct gaaaaagcca gatcgtcttc tagtcctcag cacctgaacg 1740 ttcagcagtt ggaagacatg tacaataaga tggccaagac ccaatcccaa cccatcctca 1800 ataccaagga gtcagcagca cagagcaaac caaaggaaga acttgaaatg gagagtatcc 1860 ccagccccgt agcccctctg cccactcgca cagaaggggt cattgacatg cgaagtatgt 1920 caagcattga tagtttcatt agctgtgcca cagacttccc tgaggccacc agattctccc 1980 acagcccttt gacatcactc cccagcaaga ctgggggcag cacagcccca gaagtgggct 2040 ggcggggagc tctgggtgcc agtggtggta ggtttgtgga ggccaacccc agccctgatg 2100 ccagccagca ctctagtttc ttcatcgaga gccccaagag ttccatgaaa actaacaacc 2160 ctttgaagct ccgagcactt aaagtcaact tcatggaggg tgaccccagt ccactcctcc 2220 ccgttctagg gatgtaccat gaccctctca ggaaccgggg gagtgctgcg gctgctgtcg 2280 ctggactgga gtgtgccacg cttttggaca aggctgtgct gagcccagag tcctccatct 2340 acaccacagc aagtgctaag acaccccccc ggtctcctga gaaacacaca gcaatagcgt 2400 tcaactttga ggcgggtgtc caccagtaca ttgacgcaga cacagatgat gagggacagc 2460 tgctctacag tgtggactcc agccccccca aaagcctccc tgggagcacc agtccgaagt 2520 tcagcacggg gacaagatcg gagaaaaacc actttgaaag ctccccttta cccacctccc 2580 ctaagttctt aaggcagaac tgtatttact ccacagaagc attgactgga aaaggcccca 2640 gtggtcagga aaagtgcaaa cttgagaacc acatctcccc tgacgtccgt gtgttgccag 2700 ggggaggagc ccatggaagc acacgagatc agagcatctg aactgccctg ccttggagga 2760 gagacttttg ggtgaggtcc aaagaggaga gctgttcagc ttacctgcca cagagctttt 2820 ctgcatgaac tctggaacag aaaggccctg taaagccctc agagagaaga gagactccag 2880 agaaggctcc ctaagacctt gagagccatg acaggtccat cagcatgaag ttggccaagc 2940 catagggcac agcacctcct tgtaacaact ctatagccct ctttgggaga tgacatgagt 3000 ggaactcaca gccaccacta ccaccacttt agacaggacc gaggccacat actccccatt 3060 ctctcgtggc tttccatctc agcctcggag ggcaacattg acagtcctcc tggcttcagc 3120 tagagaagga tgctggaaca agcggctggt gttgaaagag tgggttgacc aatttggtat 3180 tgaatgttgc ccagccaccc ctaggaacac ctgtccatca cctcctggat ggattccact 3240 gttagacagc tacagggaat gattggtcat ggggaagtct ctgcgccata agccacgatc 3300 ccagcgcaaa acccttactc aaatgtcttc attgacttcg gtatttcata gtacctgaga 3360 ttttattttg agataccatc agggtgagtt gcaccacttg tactcaattc taattgcccc 3420 ctggcaatct gggaagggtt cagaaggtgg gcacccagcc aacagcatga actcagagca 3480 ttgttttagg gttggaggag gaacacgctt tctttacatc actagtgtag actcaaaaga 3540 tatgcaagtg tcaaatatgc aaaagaaata gtttattcaa agagactgtg tgttactgaa 3600 gaacagcata aaaatatgat ttttttactt gcaaaaatga aaggaaaaaa ataccacgca 3660 ttgaaatgcc cagttcagac tgaataattc ctgctgcagc aaggaaagta cctactataa 3720 tagaaattct gttttgtttt ctgtggtttt caagtt 3756 19 2882 DNA Oryctolagus cuniculus 19 cctggggccg tcgggatgga ggtgagaaga cggccgtgac gcgcgcccgc gccccgcctg 60 cacgccagcg gcccgcagcg ctccctgccc ccctcgcccg ccgcagcagc gggccttgcc 120 gtcgagtgac agcggcctgg gggggcgggg ggggcggggg cggccggacc agcgatgccg 180 gcgggcatga cgaagcatgg ctcgcgctcc gccagctcgc tgccgccgga gcccatggag 240 atcgtgcgca gcaaggcgtg ctctcggcgc gtccgcctca acgtcggggg cctggcgcac 300 gaggtgctgt ggcgcaccct ggaccgcctg ccccgcacgc ggctgggcaa gctccgcgac 360 tgcaacacac acgactcgct gctcgaggtg tgtgacgact acagcctgga cgacaatgag 420 tacttcttcg accggcaccc gggcgccttc acctccatcc tcaacttcta ccgcacgggg 480 cggctgcaca tgatggagga gatgtgcgcg ctcagcttca gccaggagct tgactactgg 540 ggcatcgacg agatctacct ggagtcctgc tgccaggcgc ggtaccacca gaagaaggag 600 cagatgaatg aggaacttaa gcgcgaggcc gagacgctcc gtgagcgcga gggcgaggag 660 tttgacaaca cgtgctgcgc ggagaagcgc aagaagctgt gggacctgct ggagaagccc 720 aactcctccg tggccgccaa gatcctggcc atcatctcca tcatgttcat cgtcctctcc 780 accatcgccc tgtccctcaa cacgctgccc gagctgcaga gcctcgacga gttcggccag 840 accacggaca acccccagct ggcccacgtg gaggccgtgt gcatcgcgtg gttcaccatg 900 gagtacctgc tgcgcttcct ctcctcgccc aagaagtgga agttcttcaa gggcccgctc 960 aacgccatcg acctgctggc catcctgccc tactacgtca ccatcttcct caccgagtcc 1020 aacaagagcg tgctgcagtt ccagaacgtg cggcgcgtgg tccagatctt ccgcatcatg 1080 cgcatcctgc gcatcctgaa gctggcgcgg cactccaccg gcctccagtc cctgggcttc 1140 accctgcgga ggagctacaa cgagctgggc ttgctcatcc tcttcctcgc catgggcatc 1200 atgatcttct ccagcctcgt cttctttgcc gagaaggatg aggacgacac caagttcaaa 1260 agcatcccgg cctctttctg gtgggccacc atcaccatga cgactgtggg gtatggagac 1320 atctacccca agactctcct ggggaaaatt gtaggggggc tctgctgtat cgccggggtc 1380 ctggtgattg ctcttcccat ccccatcatc gtcaacaact tctccgagtt ctacaaggag 1440 caaaagaggc aggagaaagc gatcaagcgc agagaggctc tggagagagc caagaggaat 1500 ggcagcatcg tatccatgaa catgaaggac gctttcgccc ggagtgtcga gatgatggac 1560 atcgtggtgg agaagaacgg ggagaatttg gcgaagaagg aaaaagtaca agataaccac 1620 ttgtctccca acaagtggaa gtggacaaag aggaccctgt ccgaaaccag ctcaagtaag 1680 tcctttgaga cgaaggagca gggctcccct gagaaagcca gatcctcgtc gagtccccag 1740 cacctgaacg tgcagcagct ggaagacatg tacaacaaga tggccaagac ccagtcgcag 1800 cccgtcctca acaccaagga ggcagcggca cagagcaagc cgaaggaaga actggaaatg 1860 gagagcatcc caagccccgt ggcccctctg cccactcgca ccgagggggt catcgacatg 1920 cgaagtatgt caagcattga cagctttatc agctgtgcca cggacttccc cgaagccacc 1980 aggttctccc acagcccctt ggcttccctc cccaccaagg ctgggggcgg cgcggcccca 2040 gagctgggct ggcggggagc cctgggtgcc agcgggggcc ggctcgtgga ggccaacccc 2100 accccggatg ccagccacgg ctccggtttc ttcatcgaga gccccaagag ttccatgaag 2160 accaacaacc ccttgaagct ccgagcactc aaagtcaact ttatggccgg cgagcccggt 2220 ccactcctcc ctgtcctggg gatgtaccat gaccctctga ggacccgggg gggtgctgcg 2280 gctgctgtcg ccggcctgga gtgcgccaca ctcttggaca agcctgtgct gagcccagag 2340 tcctccatct acaccacagc gagtgcgagg acaccccccc ggtcgcccga gaagcccaca 2400 gcaatagcat tcaatttcga ggcaggcgtc caccagtaca ttgatgccga cacagatgac 2460 gagggccagc tgctctacag tgtagactcc agccctccca agagcctcca cgggggcgcc 2520 agtcccaagt gcagcatcgg ggcgaggtca gaaaagaacc actttgaaag tgccccctta 2580 cccacctccc cgaaattctt gaggcagaac tgtatttact ccacagaagg gttgactgga 2640 aaaagcctca gcggccagga aaagtgcaaa ctcgggaacc acatctcccc cgacgtccgc 2700 gtgttgccag ggggaggagc tcacgggagt actcgggatc agagcctctg aaccaccccc 2760 ccccccacct gccgtggagg ggagactgtg gccgcggccc agagtggggg ggctgttcct 2820 ctgacctgcc atagagcttt tctgcttgaa ctctgacgca gaaaagccct gcagagcccc 2880 ca 2882 20 2046 DNA Xenopus laevis 20 ttcggcacga gtggaaacaa gcctccttcc aagtcatgtt tgaaaggaaa tatgggcaaa 60 aacgaggaca gcgacaaaat tgtcattaat gttgggggta tcaggcatga gacctacagg 120 agtaccccca aaaccttgcc aggtaccaga ctctcctggc tcactgagcc tgatgccttt 180 agtaactttg actatgaccc caaaacagac gagttcttct ttgacagaca ccctcaagtc 240 tttgcctgtg tcttgaacta ctataggact gggaagctgc actgtccctc cgatgtgtgc 300 ggacccctgt acgaggaaga gttggctttt tgggggattg atgagactga tgtggaggca 360 tgttgttgga tgaattacag gcagcacagg gatgcagagg aagccctgga tagctttgag 420 actccagagc cagaggagga agaggatgga gatctgaaaa gactctgcct ccaagaagat 480 ggtagaaagc tgggctggtg gaagaggttg cggcctaaag tctgggctct ctttgaggat 540 ccctactctt caaaatatgc caggtatatc gccttagctt ccctattctt catactcatc 600 tccatcacaa cgttctgcct tgagacccat gaggcattta atgatgtcaa caacaagact 660 gaggtcttca cacaaggcaa catcactaag acggagacca tattggaaat ggagactgcg 720 ccttttctca attacgtaga aggcatttgt gtgatctggt tcacttttga gtttctaata 780 cgtgttattt tctgcccaga taaaatggag ttcattaaaa gcagcttaaa cattatagac 840 tttgtggcca ttttaccctt ctacttggaa attggcttga gtggcttgtc ttccaaagca 900 gccaaggatg ttctcggttt ccttcgggtt gttcgatttg ttaggatcct gagaatcttt 960 aagctcactc gccattttgt tgggctcagg gttcttggcc acactctacg agccagtaca 1020 aatgagtttc tccttcttat catatttttg gcacttggag ttttaatctt cgctaccatg 1080 atatactacg ccgaaaggat tggtgctgac ccagatgaca tcactggaag taagcacacc 1140 tacttcaaaa acatcccaat agggttttgg tgggctgtcg taactatgac aactttggga 1200 tatggggaca tgtacccaat gacttggtct ggcatgttgg tgggtgctct ttgtgctttg 1260 gcaggtgtgc taactattgc tatgccagtc cctgttattg tcaacaattt tggaatgtac 1320 tactcccttg ctatggctaa gcaaaagcta ccaaagaaaa agaataaaca tattccccga 1380 cctcctctac ctggatcacc caattactgt aaaccagact tgcagtctcc acatagaagt 1440 gctcaaggag atgcctgccc tttagctcag gaggaaatca ttgagatcaa cagagcagac 1500 tccaagcaga atggggatgc tgcaaatgct gcactggcca atgaagattg ccctactata 1560 gaccaggctc tgtcaccaga ggaaaagtca cctatcacgc ctggtgggag ggagagatat 1620 aatcgtgatc gtgcttgctt cctgttgacc acgggagact ttgcacattc cccagatggc 1680 aacatccgca aaggttatga aaaatcccgg agtctaaaca gcatagctgg catgagtgga 1740 aatatgctca gactgtctcc tatctccacc ccatttgggt caccatctgc agtgagacgc 1800 ccacggtctc ccattccctc catcttatag catggactca accaactgat aaggggaaca 1860 ttaactagta aatacaataa aaacaaacag acatcaacaa tggcaagaga acaaaataag 1920 agactttaac aaattctatt attttttaag tggttgatga aaaatataga ttatatgcag 1980 atatatttaa aaaaaaaagt ttggctttta aaaaaaaaaa agacaaggaa aaaaaaaaaa 2040 aaaaaa 2046 21 3591 DNA Xenopus laevis 21 atggcaacct ggaacgcatc tcagatcatc ttaaatagta tgagcaacat cattgagagc 60 ccgcaatcca aacctcgccc cgtaatggcg tccaatgggg cgtccttatt tattccagtc 120 actatggagg tgccttgtga tcaggggaca cgtatgtggt gggcattcct ggcctcttct 180 atggtgacgt ttttcggagg tctgttcatt atcctggtgt ggaggacatt caaatacctg 240 tggactgtat gttgtcactg tgggggcaaa aacaaggagg cacagaaagt tgtaaatgta 300 gcaagcagcc aggtcactga tggggactac aagccaactg atgataaaga agaagtagga 360 gtggcagaag ttggctggat gacatcagtt aaagactggg caggcgtgat gatttctgcc 420 cagaccctaa caggtcgtgt gttggttgtg acagtctttg ctctgagcat tggagcactt 480 atgatatact ttattgactc atcaaaccct attgaatctt gtcaaaactt ttacaaggat 540 ttcactcttc aaatagacat ggccttcaac atcttctttc tgctatattt tggcttgcgg 600 ttcatagctg ctaatgacaa gctttggttc tggctggaag tgaattcagt tgtggatttc 660 ttcacagtac ctcctgtgtt tgtgtcagtg tatctaaaca ggagttggct tgggctgagg 720 ttcctccgtg ctttgcggct aatacaattt tcagaaatcc tgcaattttt aaacatttta 780 aaaacaagta attccattaa gctggtgaac ctatgctcca tctttatcag tacgtggctg 840 actgcagctg gcttcatcca tttggtggag aactcaggag atccctggag aaattttgaa 900 aactcccagg acctttctta ctgggaatgt atgtacttgc tcatggtgac tatgtccaca 960 gtgggctatg gagatgttta tgcaaaaacc acccttggtc gtctcttcat ggtcttcttc 1020 attctcggcg gtttggccat gtttgccagc tacgtccccg aaatcataga gttaatagga 1080 aaccgaaaga aatatggtgg ttcatatagt gcagttagtg gacggaagca tattgtggtc 1140 tgtggtcaca tcacattaga aagcgtgtcc aacttcttga aagacttcct gcacaaggac 1200 cgagatgatg tgaatgtgga gattgtattt ttgcacaaca tatccccaaa tttggagttg 1260 gaagctttat ttaagaagca ctttactcag gtagaatttt accagggatc tgttctgaat 1320 ccacacgacc tggcaagagt taagattgag tctgcagatg cctgtctgat ccttgctaac 1380 aagtactgtg ctgaccctga tgctgaagat gcttctaaca ttatgagagt catctccatc 1440 aaaaattatc atcccaagat aagaatcatc actcagatgt tgcagtacca caataaggct 1500 cacctactta atatacccag ctggaattgg aaagatggag atgatgccat ctgccttgct 1560 gagctgaaac ttggttttat tgctcagagt tgtttggctc aaggtctatc aaccatgctg 1620 gctaatcttt tttccatgcg ttcctttatt aagattgagg aagacacctg gcaaaagtat 1680 tacctggaag gagtggccaa tgaaatgtat acagaatatt tatccagtgc ttttgtgggc 1740 ctttcattcc ctgcagtttg cgagttgtgc tttgtgaagt tgaaactgct aatgatagct 1800 atcgagtaca agtcagagaa aggagagagc aggatcttaa tcaatccggg taaccatatg 1860 aaaataaaag aaggtaccct gggatttttt attgccagtg atgccaaaga agtaaaacgg 1920 gccttttttt actgtaaagc atgtcatgat gacatcacag acccaaagcg gataaagaaa 1980 tgcgcctgca agagacttga agatgagcag ccatcagcct tgtcacccaa aaaaaagcaa 2040 cgaaatggag gaatgaggca ctctccaaac acttctccta acatgatgag gcatgatccc 2100 cttctcatga ctgggaatga tcaaattgat aatatggatt ctagcagtgt taaaagatat 2160 gattctactg gtatgttcca ctggtgtcca gccaaggaat tggataaagt gcttctgaca 2220 cggagtgaag ctgccatgac agtcctcagt gggcatgtgg ttgtctgcat ttttggagac 2280 atgacgtcgg cactgattgg agtacggaat ttggtgatgc cactgagagc cagcaatttc 2340 cattaccatg agctgaaaca tatagtcttt gttgggtccc ttgattacat taaaagagaa 2400 tgggaaacac tacacaactt cccaaaggtg tcaatattgc ctgggacacc gttaagtcga 2460 gcagatctaa gagctgtcaa cattaacctg tgtgacatgt gcgttatcct gtcagccaac 2520 cagaataata ttgatgatac atcactgcag gacaaagaat gcattttagc atctctcaac 2580 atcaaatcta tgcagtttga tgacagcata gggctcttgc aagcaaactc tcaagggttt 2640 acacccccag gtatggagag gtcatcacct gataatagcc cactgcatgg tgttgcaaga 2700 caggcatcca taactacagg agccaacatt cccataatta cagaacttgt gaacgactca 2760 aatgttcagt tcttggacca ggatgatgat gatgacccag atacagagtt atacttgact 2820 cagccctttg cctgtgggac agcatttgct gtcagtgtgt tggactccct catgagtgca 2880 acatacttca atgataacat cctgactctg atcagaactc tggtgactgg gggagcaaca 2940 ccagagctgg aagccctcgt tgcagaagag aatgctctgc gtggaggtta tagcacccca 3000 caaactctag caaacagaga ccgctgtcga gtagcccaat tagccttgta tgatggacca 3060 tttgcagatt tgggggatgg tggatgttat ggagaccttt actgcaaagc attaaaaacc 3120 tacaacatgc tgtgctttgg tatataccga ctcagagatg cccacatcag cacacccagc 3180 cagtgtacca aaaggtatgt tataaccaac cctccatatg agtttgaact ggttcccaca 3240 gacctcatct tttgcctgat gcagttcgac cataatgcca gccaatcgcg agctagcctg 3300 tctcactctt cacactcctc gcactcgtct agcaaaaaaa gttcgtctgt tacctccata 3360 ctacacacag cctcagccaa ccgtcagaac agagtcaagg ctcgagattc ccgtgacaaa 3420 caaaaaatgg gccaagcaga aaagaaatgg tatacagatg aaacggaaaa caattatccc 3480 agaaacattc agattaagcc aatgagcaca catatggcta atcagattaa tcagtacaaa 3540 tcaacaagca gcttgatacc gccaatacga gaggttgaag atgaatgtta a 3591

Claims

What is claimed is:

1. A composition of matter suitable for use in identifying chemical compounds that bind to voltage-dependent ion channel proteins, the composition comprising a screening protein that comprises an ion channel voltage sensor domain of the ion channel protein immobilized on a solid support.

2. The composition of claim 1, wherein the ion channel protein is a potassium ion channel protein.

3. The composition of claim 1, wherein the ion channel protein is a sodium ion channel protein.

4. The composition of claim 1, wherein the ion channel protein is a calcium ion channel protein.

5. The composition of claim 1, wherein the ion channel protein is an Aeropyrum pernix ion channel protein.

6. The composition of claim 5, wherein the ion channel protein is KvAP.

7. The composition of claim 1, wherein the ion channel protein is a Homo sapien ion channel protein.

8. The composition of claim 1, wherein the five N-terminal residues of the screening protein are replaced by a single leucine residue.

9. The composition of claim 1, wherein the screening protein excludes an ion conduction pore.

10. The composition of claim 1, wherein the screening protein comprises an amino acid sequence consisting essentially of the voltage sensor.

11. The composition of claim 1, wherein the solid support is a resin.

12. The composition of claim 11, wherein the resin comprises cobalt.

13. The composition of claim 11, wherein the resin comprises nickel.

14. The composition of claim 13, wherein the nickel is nickel-NTA agarose.

15. The composition of claim 11, wherein the resin comprises glutathione sepharose.

16. A kit suitable for use in identifying chemical compounds that bind to voltage-dependent ion channel proteins, the kit comprising a screening protein that comprises an ion channel voltage sensor domain of the ion channel protein and a solid support.

17. The kit of claim 16, wherein the ion channel protein is a potassium ion channel protein.

18. The kit of claim 16, wherein the ion channel protein is a sodium ion channel protein.

19. The kit of claim 16, wherein the ion channel protein is a calcium ion channel protein.

20. The kit of claim 16, wherein the ion channel protein is an Aeropyrum pernix ion channel protein.

21. The kit of claim 20, wherein the ion channel protein is KvAP.

22. The kit of claim 16, wherein the ion channel protein is a Homo sapien ion channel protein.

23. The kit of claim 16, wherein the five N-terminal residues of the screening protein are replaced by a single leucine residue.

24. The kit of claim 16, wherein the screeningl protein excludes an ion conduction pore.

25. The kit of claim 16, wherein the screening protein comprises an amino acid sequence consisting essentially of the voltage sensor.

26. The kit of claim 16, wherein the solid support is a resin.

27. The kit of claim 26, wherein the resin comprises cobalt.

28. The kit of claim 26, wherein the resin comprises nickel.

29. The kit of claim 28, wherein the nickel is nickel-NTA agarose.

30. The kit of claim 26, wherein the resin comprises glutathione sepharose.

31. A labeled screening protein suitable for use in identifying chemical compounds that bind to a voltage-dependent ion channel protein, the labeled screening protein comprising an ion channel voltage sensor domain of the ion channel protein and a detectable label.

32. The labeled screening protein of claim 31, wherein the ion channel protein is a potassium ion channel protein.

33. The labeled screening protein of claim 31, wherein the ion channel protein is a sodium ion channel protein.

34. The labeled screening protein of claim 31, wherein the ion channel protein is a calcium ion channel protein.

35. The labeled screening protein of claim 31, wherein the ion channel protein is an Aeropyrum pernix ion channel protein.

36. The labeled screening protein of claim 35, wherein the ion channel protein is KvAP.

37. The labeled screening protein of claim 31, wherein the ion channel protein is a Homo sapien ion channel protein.

38. The labeled screening protein of claim 31, wherein the five N-terminal residues of the screening protein are replaced by a single leucine residue.

39. The labeled screening protein of claim 31, wherein the screening protein excludes an ion conduction pore.

40. The labeled screening protein of claim 31, wherein the screening protein comprises an amino acid sequence consisting essentially of the voltage sensor.

41. The labeled screening protein of claim 31, wherein the detectable label is radioactive.

42. The labeled screening protein of claim 31, wherein the detectable label is colorimetric.

43. A method for screening for drug candidates that target voltage dependent ion channel protein, the method comprising:

providing a screening protein;

contacting the screening protein with a chemical compound;

determining whether the chemical compound binds to the screening protein;

wherein chemical compounds that bind to the screening protein are drug candidates.

44. A method according to claim 43, wherein the screening protein is immobilized on a solid support.

45. A method according to claim 43, wherein the chemical compound is immobilized on a solid support.

46. A method according to claim 43, wherein the chemical compound is a biological molecule.

47. A method according to claim 46, wherein the biological molecule is a polyamino acid.

48. A method according to claim 43, wherein the chemical compound is a small molecule.

49. A method according to claim 43, wherein the drug candidate alters the target voltage dependent ion channel proteins.

50. A method according to claim 43, wherein the drug candidate is a candidate for a drug useful for treating a condition mediated by aberrant electrical activity.

51. A method according to claim 50, wherein the aberrant electrical activity initiates uptake or release of neurotransmitters.

52. A method according to claim 50, wherein the aberrant electrical activity initiates contraction of muscles.

53. A method according to claim 43, wherein the drug candidate is a candidate for a drug for treating epilepsy.

54. A method according to claim 43, wherein the drug candidate is a candidate for a drug for treating arrhythmia.

55. A method according to claim 43, wherein the drug candidate is further tested for activity against a condition mediated by aberrant electrical activity.

56. A method according to claim 55, wherein the aberrant electrical activity initiates uptake or release of neurotransmitters.

57. A method according to claim 55, the aberrant electrical activity initiates contraction of muscles.

58. A method according to claim 43, wherein the drug candidate is further tested for activity against epilepsy.

59. A method according to claim 43, wherein the drug candidate is further tested for activity against arrhythmia.